α-Phenylethyl substituted bis(pivaloyloxymethyl) ester analogues of fosmidomycin and FR900098

Article abstract of DOI:10.1071/CH07018

α-Phenylethyl substituted bis(pivaloyloxymethyl) ester analogues of the natural products Fosmidomycin and FR900098 have been synthesized, and their in vitro antimalarial activity determined. The ?-phenylethyl substituted Fosmidomycin analogue displays mod

Full text of DOI:10.1071/CH07018

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2007, 60, 154–158
www.publish.csiro.au/journals/ajc
α-Phenylethyl Substituted Bis(pivaloyloxymethyl) Ester
Analogues of Fosmidomycin and FR900098
Thomas Kurz,A,C Christoph Behrendt,A Uwe Kaula,A Bärbel Bergmann,B
and Rolf D. WalterB
AInstitute of Pharmacy, University of Hamburg, Bundesstraße 45, 20146 Hamburg, Germany.
BBernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Straße 74,
D-20359 Hamburg, Germany.
CCorresponding author. Email: kurz@chemie.uni-hamburg.de
α-Phenylethyl substituted bis(pivaloyloxymethyl) ester analogues of the natural products Fosmidomycin and FR900098
have been synthesized, and their in vitro antimalarial activity determined. The α-phenylethyl substituted Fosmidomycin
analogue displays moderate in vitro antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium
falciparum.
Manuscript received: 22 January 2007.
Final version: 23 February 2007.
O
P
OH
N
O
P
OH
N
Introduction
HO
HO
HO
HO
R
R
According to estimations by the World Health Organisation,
1.5 to 2.7 million people die of malaria every year. Since the
widespread resistance of Plasmodium falciparum, the causative
agent of Malaria tropica, complicates an efficient therapy, novel
antimalarial drugs based on new modes of action are urgently
needed. A promising metabolic pathway for the development
of novel antimalarials, antibiotics, and herbicides represents the
DOXP/MEP pathway of isoprenoid biosynthesis, which is, for
instance, present in Plasmodium falciparum, several pathogenic
bacteria, and higher plants, but is absent in humans.[1] The
natural products Fosmidomycin 1 and FR900098 2 (Fig. 1)
are potent inhibitors of the 1-desoxy-d-xylulose-5-phosphate
reductoisomerase (DXR), a key enzyme of the DOXP/MEP
pathway.[2] Currently Fosmidomycin is in clinical phase II tri-
als in combination with the lincosamide antibiotic Clindamycin
for the treatment of Malaria tropica.[3] However, a drawback of
Fosmidomycin represents its relatively poor oral bioavailability
of approximately 30%.[4] Furthermore, most phosphonohydrox-
amic acids prepared so far are of a hygroscopic nature, which
makes their use and analysis difficult.[5]
O
O
α-Phenylfosmidomycin 3 R ϭ H
α-PhenylFR900098 R ϭ Me
Fosmidomycin 1 R ϭ H
FR900098 2 R ϭ Me
O
O
P
O
OH
N
R
O
O
O
O
O
Target compounds: R ϭ H, Me
Fig. 1. Fosmidomycin and analogues.
In previous studies, we and other groups[5] have discovered
that the phosphonic acid moiety of the lead compounds 1 and
2 as well as their hydroxamic acid functionality are essential
for distinct antimalarial activity.[5–7] Moreover, Schlitzer and
coworkers have shown that prodrugs of FR9000098, a more
active analogue of Fosmidomycin, display improved in vivo
antimalarial activity against Plasmodium vinckei in the mouse
model.[7] Recently, we reported that α-phenylfosmidomycin 3
(ic50 0.4 µM) exhibits potent activity against the chloroquine-
resistant strain Dd2 of Plasmodium falciparum.[8a,b] Later, Van
Calenbergh et al. confirmed the high antimalarial activity of
α-aryl substituted Fosmidomycin analogues.[9] Furthermore,
Schlitzer and our group have discovered that the hygroscopicity
of phosphonohydroxamic acids can be overcome by masking the
phosphonic acid moiety as a bis(pivaloyloxymethyl) ester.[6,7]
We have shown that the non-hygroscopic bis(pivaloyloxymethyl)
ester of 3 displays an ic50 value of 0.6 µM towards the
chloroquine-sensitive strain 3D7 of Plasmodium falciparum and
is approximately as active as the bis(pivaloyloxymethyl) ester
of FR900098 2.[5] In addition, α-arylmethyl substituted Fos-
midomycin analogues recently prepared in our group display
antimalarial activity in the micromolar range.[5]
In order to expand the general knowledge of the structure–
activity relationships, and to overcome the relatively poor
bioavailability and the hygroscopicity of Fosmidomycin, we now
describe the synthesis and antimalarial activity of α-phenylethyl
substituted bis(pivaloyloxymethyl)ester analogues of the lead
compounds 1–3.
© CSIRO 2007
10.1071/CH07018
0004-9425/07/030154

Analogues of Fosmidomycin and FR900098
155
Table 1. Inhibition of P. falciparum growth [%] at 100, 10, and 1 µM
O
P
O
O
EtO
O
EtO
P
(a)
Inhibition of P. falciparum growth [%]A
EtO
Compound no.
EtO
O
O
4
100 µM
10 µM
1 µM
5
Ph
3
11
12
100
100
100
89
42
13
65
4
4
(b)
O
P
OBn
N
O
P
(c)
H
EtO
EtO
R
EtO
N
AMean values of two independent determinations.
OBn
EtO
O
6
Ph
Biological Activity
Ph
The in vitro antimalarial activity of compounds 11 and 12
was evaluated by an 8-[3H]hypoxanthine incorporation assay
according to the method of Desjardins using the chloroquine-
sensitive strain 3D7 of Plasmodium falciparum.[11] Inhibition
of Plasmodium falciparum growth at 100, 10, and 1 µM
has been determined. The bis(pivaloyloxymethyl) ester of
α-phenylfosmidomycin 3 was used as reference compound
(Table 1). During the determination the bis(pivaloyloxymethyl)
esters were converted into phosphonic acids by non-specific
esterases.
The replacement of the phenyl nucleus of 3 by a phenylethyl
group led to a significant reduction of antimalarial activity.
In contrast to the higher activity of FR900098 compared to
Fosmidomycin the formyl derivative 11 is more active than the
acetyl derivative 12.[5–7]
7 R ϭ H
8 R ϭ Me
(d), (e)
O
O
O
OBn
N
O
P
R
O
O
O
(f)
Ph
O
9 R ϭ H
10 R ϭ Me
O
O
OH
O
O
P
N
R
O
O
O
Ph
O
Conclusions
11 R ϭ H
12 R ϭ Me
This paper reports the structural modification of α-phenyl-
fosmidomycin 3, a synthetic and highly active analogue of
Fosmidomycin 1. The phenyl nucleus of 3 was successfully
replaced by a phenylethyl group. Due to their hygroscopicity the
phosphonic acids were converted into stable, non-hygroscopic
bis(pivaloyloxymethyl) esters. However, the new analogues 11
and 12 are significantly less active than the lead compounds 1–3.
As observed in case of other α-substituted analogues previously
prepared in our group, the formyl derivative 11 was more active
than the acetyl derivative 12.[5] Since the bis(pivaloyloxymethyl)
esters are converted into the corresponding free phosphonic
acids by esterases during the assay, no animal experiments have
been necessary.
Scheme 1. Synthesis of α-phenylfosmidomycin analogues. Reagents:
(a) BunLi, Ph(CH2)2Cl; (b) HCl, BnONH2, NaCNBH3; (c) HOOCH/Ac2O
or Ac2O; (d) TMSBr, THF, H2O; (e) ClCH2OOCC(CH3)3, Et3N; (f) H2,
Pd–C, MeOH.
Results and Discussion
Chemistry
Starting material 4 was prepared according to a literature
procedure.[10] Synthesis of the target compounds 11 and 12
was conducted as reported previously for the preparation of
α-hydroxymethyl- and α-arylmethyl-substituted Fosmidomycin
analogues.[5]
Experimental
Elemental analyses were carried out with a Heraeus CHN-O-
Rapidinstrument. IRspectrawererecordedonaShimadzuFT-IR
Alkylation of dioxolane 4 with 2-phenylethyl chloride in
presence of BunLi in dry toluene afforded the corresponding
phenylethyl substituted dioxolane 5. The O-benzyl-protected
hydroxylamine 6 was obtained by dioxolane hydrolysis, oxi-
mation, and subsequent reduction of the intermediate oximes
with sodium cyanoborohydride in acidic medium. Acetylation
or formylation of 6 led to protected formo- and aceto-
hydroxamic acids 7 and 8. Treatment of 7 and 8 with bro-
motrimethyl silane and water furnished the corresponding
hygroscopic phosphonic acids, which were directly transformed
into their bis(pivaloyloxymethyl)esters 9 and 10 by alkyla-
tion with chloromethyl pivalate in dry DMF. Finally, the
O-benzyl group was removed in almost quantitative yields by
catalytic hydrogenation to give the novel analogues 11 and 12
(Scheme 1). All compounds were characterized by elemental
analysis or mass spectrometry, and IR, 1H NMR, and 13C NMR
spectroscopy.
1
8300. H (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a BrukerAMX 400 spectrometer using tetramethyl-
silane as internal standard and d6-DMSO or CDCl3 as solvents.
Mass spectra were recorded on a Micromass VG 70–250S mass
spectrometer (HRFAB), a Finnigan MAT 311 A mass spectrom-
eter (EI), or a Varian MS 1200L mass spectrometer (ESI).
Chemistry
General Procedure for the Preparation of
(1-[1,3]Dioxolan-2-ylmethyl-3-phenylpropyl)-
phosphonic Acid Diethyl Ester 5
A solution of compound 4 (20 mmol) in dry toluene (30 mL)
was cooled to −78◦C, treated with n-butyllithium (20 mmol,
2.7 M solution in heptane), and stirred for 1 h. 2-Phenylethyl
chloride (30 mmol) was added in one portion and the mixture

156
T. Kurz et al.
was allowed to warm to room temperature. After being stirred
overnight, an aqueous solution of NH4Cl (10%, 100 mL) was
added, and the product extracted with EtOAc (2 × 50 mL). The
organic layer was dried over Na2SO4, evaporated, and the result-
ing residue purified by column chromatography on silica gel
(EtOAc) to give compound 5 as colourless oil (56%). Calc.
for C17H27NO5P [M + H]+: 343.1674. Found: 343.1667. νmax
(KBr)/cm−1 1240 (P=O). δH (d6-DMSO) 7.30–7.26 (m, 2H),
7.20–7.16 (m, 3H), 4.97 (t, 1H, J 5.1), 4.03–3.95 (m, 4H), 3.90–
3.84 (m, 2H), 3.79–3.73 (m, 2H), 2.76–2.63 (m, 2H), 1.99–1.67
(m, 5H), 1.23 and 1.22 (2t, 6H, J 7.1). δC (d6-DMSO) 142.04,
oil (94%). Calc. for C23H32NO5P [M + H]+: 434.2096. Found:
434.2120. νmax (KBr)/cm−1 1678 (C=O), 1233 (P=O). δH (d6-
DMSO) 8.29–7.90 (br s, 1H), 7.45–7.35 (m, 5H), 7.30–7.26 (m,
2H), 7.20–7.17 (m, 3H), 4.91 (s, 2H), 4.04–3.94 (m, 4H), 3.78–
3.52 (m, 2H), 2.72–2.60 (m, 2H), 1.99–1.63 (m, 5H), 1.21 and
1.20 (2t, 6H, J 7.1). δC (CDCl3) 162.98, 141.35, 134.33, 129.47,
129.11, 128.74, 128.47, 126.07, 77.68, 61.74 (d, 2JCP 6.6), 61.72
(d, 2JCP 7.1), 42.37, 33.43 (d, 3JCP 9.7), 32.96 (d, 1JCP 139.4),
30.25, 25.67, 16.52 (d, 3JCP 5.6).
General Procedure for the Preparation of [3-(Acetyl-
benzyloxyamino)-1-phenethylpropyl]phos-
phonic Acid Diethyl Ester 8
2
128.68, 128.66, 126.19, 102.61 (d, JCP 11.7), 64.63, 64.54,
2
3
2
61.48 (d, JCP 6.6), 33.21 (d, JCP 7.6), 32.78 (d, JCP 3.1),
31.09 (d, 1JCP 138.9), 30.93 (d, 2JCP 4.1), 16.67 (d, 2JCP 5.6).
Acetic acid anhydride (20 mmol) was added to a solution of
hydroxylamine 6 (10 mmol) in dry THF (10 mL), and the mix-
ture stirred at room temperature for 2 h. After addition of EtOAc
(100 mL), the organic layer was washed with aqueous KOH
(0.1 M, 2 × 50 mL), water (50 mL), and three times with aqueous
HCl (1 M).The organic layer was dried over MgSO4, evaporated,
and the residue was purified by column chromatography on sil-
ica gel (EtOAc) to give compound 8 as pale yellow oil (83%).
Found: C 64.0, H 7.8, N 3.5. C24H34NO5P requires C 64.4,
H 7.7, N 3.1%. νmax (KBr)/cm−1 1661 (C=O), 1233 (P=O). δH
(d6-DMSO) 7.45–7.35 (m, 5H), 7.30–7.26 (m, 2H), 7.20–7.16
(m, 3H), 4.88 (s, 2H), 4.04–3.94 (m, 4H), 3.81–3.63 (m, 2H),
2.72–2.59 (m, 2H), 2.02 (s, 3H), 1.99–1.63 (m, 5H), 1.21 and
1.20 (2t, 6H, J 7.1). δC (CDCl3) 172.20, 141.47, 134.45, 129.25,
General Procedure for the Preparation of (3-Benzyl-
oxyamino-1-phenethylpropyl)phosphonic
Acid Diethyl Ester 6
The acetal 5 (30 mmol) was refluxed with water (40 mL), HCl
(1 mL, 37%), and acetone (100 mL) for 90 min. After the mix-
ture was cooled to room temperature, the acetone was removed,
water (200 mL) was added, and the mixture extracted with
dichloromethane (3 × 100 mL).The organic layer was dried over
Na2SO4 and then evaporated.
A solution of the remaining aldehyde in MeOH (40 mL) was
treated with O-benzylhydroxylamine (30 mmol) and stirred at
room temperature for 1 h. MeOH (430 mL) was then added and
the resulting solution treated with NaBH3CN (90 mmol). HCl
(37%, 30 mL) was added dropwise over 30 min under ice cool-
ing. The mixture was allowed to warm to room temperature,
and treated with additional NaBH3CN (20 mmol). After an total
time of 2 h, the solution was concentrated, and aqueous KOH
(10%) was added under ice cooling until an alkaline reaction was
observed. The aqueous solution was extracted three times with
CH2Cl2 (50 mL). The organic layers were combined, dried with
MgSO4, and evaporated. The residue was purified by column
chromatography on silica gel (95:5 EtOAc/MeOH) to give com-
pound 6 as a colourless oil (78%). Found: C 65.0, H 8.0, N 3.7.
C22H32NO4P requires C 65.2, H 8.0, N 3.5%. νmax (KBr)/cm−1
3243 (N–H), 1235 (P=O). δH (d6-DMSO) 7.35–7.25 (m, 7H),
7.19–7.16 (m, 3H), 6.63 (t, 1H, J 5.9), 4.59 (s, 2H), 4.03–3.93
(m, 4H), 2.94–2.82 (m, 2H), 2.74–2.60 (m, 2H), 1.91–1.76
(m, 3H), 1.72–1.56 (m, 2H), 1.22 and 1.21 (2t, 6H, J 7.1). δC (d6-
DMSO)142.06, 138.84, 128.72, 128.60, 128.55, 128.45, 128.37,
127.75, 126.21, 75.47, 61.29 (d, 2JCP 7.1), 49.48 (d, 3JCP 8.7),
2
128.96, 128.70, 128.49, 128.42, 125.98, 76.30, 61.66 (d, JCP
7.1), 43.65, 33.42 (d, 3JCP 10.2), 33.05 (d, 1JCP 139.4), 30.22 (d,
2JCP 3.1), 25.55, 20.56, 16.52 (d, 3JCP 6.1), 16.49 (d, 3JCP 6.1).
General procedure for the Preparation of
[3-(Benzyloxyformylamino)-1-phenethylpropyl]-(2,2-
dimethylpropionyloxymethoxy)phosphinoyloxymethyl
Ester 9 and
[3-(Benzyloxyacetylamino)-1-phenethylpropyl]-(2,2-
dimethylpropionyloxymethoxy)phosphinoyloxymethyl
Ester 10
Trimethylsilylbromide(15 mmol)wasaddedtoastirredsolu-
tion of phosphonic acid diethyl esters 7 or 8 (3 mmol) in dry
CH2Cl2 (10 mL) at 0◦C. After 1 h, the solution was allowed
to warm to room temperature and stirred for 24 h. The solvent
was removed under reduced pressure, and the residue was dis-
solved in THF (10 mL) and treated with water (0.1 mL). After
5 min, the solvent was evaporated and the residue was dried
in vacuo overnight. For the alkylation step, the resulting oil
was dissolved in anhydrous DMF (20 mL), treated with triethyl-
amine (9 mmol), and stirred for 5 min. Chloromethyl pivalate
(30 mmol) was added and the mixture was stirred at 70◦C for 2 h.
Another 3 mmol of triethylamine and 5 mmol of chloromethyl
pivalate were added, and the solution was stirred for 2 h.The pro-
cedure of adding triethylamine and chloromethyl pivalate was
repeated once again. After an overall time of 6 h, the mixture
was allowed to cool and stirred overnight at room temperature.
Diethyl ether (100 mL) was added, and the solution was succes-
sively washed with water (50 mL), saturated aqueous NaHCO3
solution (2 × 50 mL), and again with water (50 mL).The organic
layer was dried over MgSO4 and the solvent was removed under
reduced pressure.The resulting oil was purified by column chro-
matography on silica gel (Et2O) to give compounds 9 and 10 as
colourless products.
3
1
2
33.12 (d, JCP 8.7), 32.62 (d, JCP 138.4), 30.52 (d, JCP 3.1),
25.89 (d, 2JCP 3.1), 16.70 (d, 3JCP 5.6).
General Procedure for the Preparation of [3-(Benzyl-
oxyformylamino)-1-phenethylpropyl]phosphonic
Acid Diethyl Ester 7
Formic acid (500 mmol) was treated with acetic acid anhy-
dride (50 mmol), and the mixture stirred under exclusion
of humidity. After 20 min, the solution was cooled to 0◦C, and
the hydroxylamine 6 (10 mmol), dissolved in dry THF (20 mL),
was added dropwise. After 10 min, the mixture was allowed
to warm to room temperature and stirred for another hour.
The solution was treated with EtOAc (200 mL), and succes-
sively washed with water (3 × 50 mL), aqueous KOH (0.1 M,
3 × 25 mL), and once again with water. The organic layer was
dried over MgSO4 and the solvent was removed under reduced
pressure. The residue was purified by column chromatography
on silica gel (EtOAc) to give compound 7 as a pale yellow
Compound 9 was obtained as a colourless oil (37%). Found:
C 61.2, H 7.3, N 2.5. C31H44NO9P requires C 61.5, H 7.3,

Analogues of Fosmidomycin and FR900098
157
N 2.3%. νmax (KBr)/cm−1 1753 (C=O, ester), 1680 (C=O,
hydroxamate), 1255 (P=O). δH (CDCl3) 8.27–7.88 (br s, 1H),
7.44–7.24 (m, 7H), 7.21–7.13 (m, 3H), 5.63 (ddd, 4H, 3JHP 12.5,
JAB 7.9), 4.90 (s, 2H), 3.74–3.53 (m, 2H), 2.68–2.58 (m, 2H),
1.99–1.60 (s, 5H), 1.14 and 1.13 (2s, 18H). δC (CDCl3) 176.86,
162.99, 140.88, 134.34, 130.88, 129.54, 129.14, 128.81, 128.77,
128.51, 128.44, 126.18, 81.51, 77.65, 42.09, 38.73, 33.70 (d,
1JCP 138.4), 33.26 (d, 3JCP 9.7), 29.78, 26.86, 25.30.
group A positive), RPMI 1640 medium supplemented with
25 mM HEPES, 20 mM sodium bicarbonate, and 0.5% Albu-
MAX (Invitrogen, Karlsruhe, Germany) at 5% hematocrit. The
flasks were gassed with 90% N2, 5% O2, and 5% CO2, and
incubated at 37◦C. The development of the cultures and the per-
centage of infected red blood cells were determined by light
microscopy of Giemsa-stained thin smears.
Compound 10 was obtained as a colourless oil (70%). Found:
C 61.7, H 7.5, N 2.2. C32H46NO9P requires C 62.0, H 7.5,
N 2.3%. νmax (KBr)/cm−1 1753 (C=O, ester), 1666 (C=O,
hydroxamate), 1252 (P=O). δH (CDCl3) 7.45–7.37 (m, 5H),
Preparation of Drug Solutions
The respective compounds (20 µmol) were dissolved in
DMSO (400 µL) and further diluted with water/ethanol (50:50)
to obtain the particular concentration.
3
7.29–7.26 (m, 2H), 7.20–7.14 (m, 3H), 5.62 (ddd, 4H, JHP
12.7, JAB 7.1), 4.87 (s, 2H), 3.77–3.60 (m, 2H), 2.68–2.59 (m,
2H), 2.00 (s, 3H), 1.98–1.61 (m, 5H), 1.13 and 1.12 (2s, 18H).
δC (CDCl3) 176.82, 172.26, 140.99, 134.40, 129.31, 128.97,
128.71, 128.45, 126.07, 81.45 (d, 2JCP 7.1), 76.34, 43.42, 38.71,
33.70 (d, 1JCP 138.4), 33.20 (d, 3JCP 10.2), 29.75 (d, 2JCP 3.1),
26.84, 25.13 (d, 2JCP 2.0), 20.51.
Determination of Parasite Growth Inhibition
The tests were carried out in 96-well microtitre plates under
strict aseptic conditions, according to the literature. Dilutions
of each compound were added to a suspension (250 µL) of
P. falciparum infected erythrocytes (1.5% hematocrit, 1.5–2%
parasitemia). The plates were flushed with a gas mixture con-
sisting of 90% N2, 5% O2, and 5% CO2, closed tightly and
incubated at 37◦C for 24 h. Afterwards, 0.1 µCi of 8-[3H]-
hypoxanthine was added to each well. The plates were flushed
with the above-mentioned gas mixture, incubated for an addi-
tional 24 h at 37◦C, and subsequently harvested with a cell
harvester system (Inotech, Dottikon, Switzerland). Infected ery-
throcytes were washed four times with distilled water before they
were analyzed for incorporated radioactivity in a multidetector
liquid scintillation counter (Wallac, Turku, Finland).
General Procedure for the Preparation of
[3-(Formylhydroxyamino)-1-phenethylpropyl]-(2,2-
dimethylpropionyloxymethoxy)phosphinoyloxymethyl
Ester 11 and
[3-(Formylhydroxyamino)-1-phenethylpropyl]-(2,2-
dimethylpropionyloxymethoxy)phosphinoyloxymethyl
Ester 12
The O-protected hydroxamic acid 9 or 10 (10 mmol) was
dissolved in methanol (50 mL). After addition of the Pd–C cat-
alyst, hydrogen gas was added to generate a pressure of 2 bar,
and the mixture was hydrogenated for 1 h. The suspension was
filtered through an SPE tube RP-18 purchased from Supelco.
The filtrate was evaporated to give compounds 11 and 12 as
colourless oils.
References
[1] (a) T. Kuzuyama, S. Takahashi, M. Takagi, H. Seto, J. Biol. Chem.
2000, 275, 19928. doi:10.1074/JBC.M001820200
(b) W. Eisenreich, F. Rohdich, A. Bacher, Trends Plant Sci. 2001, 6,
78. doi:10.1016/S1360-1385(00)01812-4
Compound 11 was obtained as a colourless oil (99%). Found:
C 56.0, H 7.7, N 2.9. C24H38NO9P requires C 55.9, H 7.4,
N 2.7%. νmax (KBr)/cm−1 1754 (C=O, ester), 1673 (C=O,
hydroxamate), 1251 (P=O). δH (d6-DMSO) 10.04 (s, 0.5H),
9.60 (s, 0.5H), 8.24 (s, 0.5H), 7.88 (s, 0.5H), 7.31–7.25 (m, 2H),
(c)M. Rohmer, Nat. Prod. Rep. 1999, 16, 565. doi:10.1039/A709175C
[2] H. Jomaa, J. Wiesner, S. Sanderbrand, B. Altincicek, C. Weidemeyer,
M. Hintz, I. Turbachova, M. Zeidler, H. K. Lichtenthaler, D. Soldati,
E. Beck, Science 1999, 285, 1573. doi:10.1126/SCIENCE.285.
5433.1573
3
7.21–7.15 (m, 3H), 5.63 (ddd, 2H, JHP 12.4, JAB 8.1), 3.64–
[3] (a) B. Lell, R. Ruangweerayut, J. Wiesner, M. A. Missinou,
A. Schindler, T. Baranek, M. Hintz, D. Hutchinson, H. Jomaa,
P. G. Kremsner, Antimicrob. Agents Chemother. 2003, 47, 735.
doi:10.1128/AAC.47.2.735-738.2003
3.45 (m, 2H), 2.73–2.59 (m, 2H), 2.00–1.59 (m, 5H), 1.15 and
1.14 (2s, 18H). δC (CDCl3) 176.91, 176.89, 163.53, 140.62 (d,
3JCP 10.2), 128.59, 128.42, 128.34, 126.30, 81.83 (d, 2JCP 7.1),
44.81 (d, 3JCP 4.1), 38.74, 34.00 (d, 1JCP 137.4), 33.55 (d, 3JCP
13.2), 30.78 (d, 2JCP 4.1), 26.84, 24.50 (d, 2JCP 3.1).
(b) S. Borrmann, I. Lundgren, S. Oyakhirome, B. Impouma,
P.-B. Matsiegui,A.A.Adegnika, S. Issifou, J. F. J. Kun, D. Hutchinson,
J. Wiesner, H. Jomaa, P. G. Kremsner, Antimicrob. Agents Chemother.
2006, 50, 2713. doi:10.1128/AAC.00392-06
Compound 12 was obtained as a colourless oil (100%).
Found: C 56.4, H 7.8, N 2.7. C25H40NO9P requires C 56.7,
H 7.6, N 2.6%. νmax (KBr)/cm−1 1752 (C=O, ester), 1654
(C=O, hydroxamate), 1232 (P=O). δH (d6-DMSO) 9.77 (s, 1H),
7.31–7.25 (m, 2H), 7.15 (m, 3H), 5.63 (ddd, 3JHP 12.7, JAB 7.1),
3.68–3.47 (m, 2H), 2.71–2.59 (m, 2H), 1.99–1.62 (m, 8H), 1.15
and 1.14 (2s, 18H). δC (CDCl3) 176.87, 176.82, 172.80, 140.69,
128.57, 128.35, 126.25, 81.77 (d, 2JCP 6.1), 81.49 (d, 2JCP 7.1),
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