Synthesis of α-aryl-substituted and conformationally restricted fosmidomycin analogues as promising antimalarials

Article abstract of DOI:10.1002/ejoc.200600202

Fosmidomycin represents a new antimalarial drug that acts by inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an essential enzyme of the mevalonate-independent pathway of isoprenoid biosynthesis. This work describes the synthesis of a series

Full text of DOI:10.1002/ejoc.200600202

FULL PAPER
DOI: 10.1002/ejoc.200600202
Synthesis of α-Aryl-Substituted and Conformationally Restricted Fosmidomycin
Analogues as Promising Antimalarials
Timothy Haemers,[a] Jochen Wiesner,[b] Roger Busson,[c] Hassan Jomaa,[b] and
Serge Van Calenbergh*[a]
Keywords: Fosmidomycin / 1-Deoxy--xylulose 5-phosphate reductoisomerase / α-Aryl-substituted phosphonate /
Rigidified analogues
Fosmidomycin represents a new antimalarial drug that acts
by inhibition of 1-deoxy- -xylulose 5-phosphate reductoiso-
merase, an essential enzyme of the mevalonate-independent
pathway of isoprenoid biosynthesis. This work describes the
synthetic route involving a 3-aryl-3-phosphorylpropanal in-
termediate proved practical to prepare these derivatives. A
phospha-Michael addition to cyclopent-2-enone gave access
to conformationally restricted analogues.
D
synthesis of a series of α-aryl-substituted fosmidomycin ana- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
logues that exhibit improved antimalarial activity. A linear
Germany, 2006)
ties. To study the structure-activity relationships, hy-
droxamic moiety modifications, including benzoxazolone
and oxazolopyridinone functionalities, have been re-
ported.[7] Also, the phosphonate moiety has been altered to
produce prodrugs with improved oral bioavailability.[8–10]
Surprisingly, modifications addressing the three-carbon
spacer are scarce. Recently, we reported the discovery of
a series of α-aryl-substituted fosmidomycin or FR900098
derivatives, 1 and 2 (Figure 1), which generally proved supe-
rior to fosmidomycin in inhibiting P. falciparum growth.[11]
To sort out the influence of the lipophilicity and electronic
properties of this phenyl moiety, substituents were intro-
duced according to Topliss’ methodology.[12] Briefly, in this
methodology an operational scheme is used to quickly
identify the optimum substitution on a benzene ring for
maximizing drug potency by virtue of resulting changes in
hydrophobic, electronic and steric effects.
Here, we describe the detailed procedure used to synthe-
size these α-substituted analogues. Although strategies to
synthesise products with a C–P bond are well documen-
ted,[13] introducing aryl substituents in the α-position of a
phosphonate [resulting in a P–CH(Ar)–C motif] is quite
challenging. Fosmidomycin was first synthesised in the
early 1980s by Hemmi et al. using a Michaelis–Becker reac-
tion.[14] This approach cannot be easily adapted to allow
the synthesis of α-substituted derivatives.
Introduction
In the 1970s, Okuhura and colleagues reported the first
isolation of fosmidomycin as a structurally simple antibiotic
from Streptomyces lavendulae. In recent years, fosmidomy-
cin received considerable attention due to its promising an-
timalarial activity, and recent clinical trials conducted in
Gabon and Thailand confirmed the potential of fosmido-
mycin as an antimalarial drug.[1,2] In 1998, the molecular
target of fosmidomycin was discovered to be 1-deoxy--xy-
lulose 5-phosphate (DOXP) reductoisomerase.[3,4] This en-
zyme plays an essential role in the mevalonate-independent
pathway for the synthesis of isoprenoids, and is absent in
humans.[5] Fosmidomycin was found to be a potent inhibi-
tor for the DOXP reductoisomerase (DXR) of P. falcipa-
rum.[6] After this important discovery, much attention has
been focused on the chemical synthesis of fosmidomycin
analogues. FR900098, the acetyl analogue of fosmidomy-
cin, was shown to be approximately twice as active against
P. falciparum in vitro, as well as in a P. vinckei mouse
model.[6]
Chemical variations of fosmidomycin were mainly di-
rected to increase the inhibitory activity against DXR or to
achieve inhibitors with improved physicochemical proper-
[a] Laboratory for Medicinal Chemistry (FFW), Ghent University,
Harelbekestraat 72, 9000 Gent, Belgium
Fax: +32-9-264-8146
E-mail: serge.vancalenbergh@ugent.be
In this study, 3-aryl-substituted 3-phosphorylpropanals
were anticipated to be appropriate intermediates for the
synthesis of a small series of α-aryl-substituted fosmidomy-
cin analogues. Depending on the availability of the starting
material, a lithiation/allylation/alkene oxidation sequence
or a Michael addition will be considered for the synthesis
of these intermediates (Scheme 1). A drawback of this strat-
[b] Universitätsklinikum Giessen und Marburg, Institut für Klinis-
che Chemie und Pathobiochemie,
Gaffkystrasse 11, 35392 Giessen, Germany
[c] Laboratory for Medicinal Chemistry, Rega Institute, Catholic
University of Leuven,
Minderbroedersstraat 10, 3000 Leuven, Belgium
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Synthesis of Fosmidomycin Analogues as Promising Antimalarials
FULL PAPER
Figure 1. Structures of fosmidomycin, FR900098 and analogues under study.
Scheme 1. Retrosynthetic route toward analogues 1 and 2.
egy is that every derivative has to be synthesized de novo,
which does not permit preparation of an extended series of
the envisaged analogues. However, when the proposed
routes give the desired analogues in good overall yields,
they might be valuable for scale-up purposes, e.g., to pre-
pare a selected inhibitor for in vivo studies. Interestingly,
when applied to cyclopent-2-enone, the Michael addition
should be a useful approach in designing unprecedented
fosmidomycin analogues 3 and 4, in which the three-carbon
spacer is part of a cyclopentane ring. Indeed, by incorporat-
ing the α- and β-carbon atoms into a cyclopropane ring, we
recently demonstrated that rigidification of fosmidomycin
might result in potent DXR inhibitors.[15]
Results and Discussion
Synthesis of α-Aryl-Substituted Fosmidomycin and
FR900098 Analogues
Retrosynthetic analysis toward the synthesis of the de-
sired α-substituted fosmidomycin analogues is depicted in
Scheme 1.
Two synthetic pathways toward the aldehyde synthons
were followed (Scheme 2). The first one started from the
appropriate diethyl benzylphosphonate, which upon treat-
Scheme 2. Reagents and conditions: (a) (i) nBuLi, THF, –50 to
–70 °C, (ii) allyl bromide, –70 °C; (b) (i) OsO4, 4-methylmorpholine
N-oxide, dioxane (ii) NaIO4; (c) triethyl phosphite, phenol, 100 °C;
ment with nBuLi in the presence of allyl bromide, afforded
6a,b in 97 and 33% yields, respectively.[16] Oxidation of 6a,b
to the vicinal cis-diol with osmium tetraoxide in the pres- (d) 2  HCl, room temperature.
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FULL PAPER
ence of 4-methylmorpholine N-oxide, followed by sodium signing these compounds as the desired product and the
periodate cleavage gave aldehydes 9a,b, which could be used corresponding deoxygenated derivative, i.e. the amide. Fur-
in the next step without further purification.
ther structural evidence for this deoxygenation was fur-
1
When the desired benzylphosphonate was not commer- nished by a H COSY NMR spectrum of the side product,
cially available, an alternative strategy to prepare the de- which shows a strong coupling between the NCH2 protons
sired aldehydes was followed. A 1,4-addition of triethyl and a heteroatom-bound proton at δ = 7.04 ppm. This
phosphite to the appropriately substituted cinnamaldehyde coupling is normally absent in the desired products, as may
in the presence of phenol gave the acetals 8c–e in 70–85% be expected for such long-range 4J(CH2NOH) coupling.
yield.[17] Subsequent deprotection of the diphenyl acetal af- Also, the characteristic 13C NMR upfield shifts of the N–
forded in 76–83% yield the corresponding aldehydes, which CH2 carbon signal are in agreement with the absence of
appeared stable enough to be purified by flash chromatog- the OH group on the nitrogen atom (β-substituent effect).
raphy. If necessary, substituted cinnamaldehydes were syn- Indeed, for the deoxygenated product the N–CH2 signal ap-
thesized. In our hands a palladium-catalyzed synthesis from peared at δ = 35.8 ppm, while for product 14c two signals
acrolein diethyl acetal and the corresponding aryl iodide at δ = 47 and 44 ppm were found. This indicates that 14c
was very efficient.[18] Only the (E) isomer was obtained, as (and also 14e) exists as a mixture of syn- and anti-NOH
deduced from the large coupling (16 Hz) between the vi- rotamers in a 2:1 ratio.
nylic hydrogen atoms.
Compounds 14c,e and 15a–e were finally deprotected
Conversion of the appropriate aldehydes to the desired with 4 equiv. of TMSBr in CH2Cl2 at ambient temperature
analogues 1 and 2 is depicted in Scheme 3. Treatment of to afford pure 1c,e and 2a–e after purification by reversed-
9a–e with O-benzylhydroxylamine yielded (67–92%) oximes phase HPLC. Although this reaction was almost quantita-
10a–e. 13C NMR spectroscopy revealed the presence of two tive, minor amounts of deacylated products were detected,
geometric isomers, which were reduced with sodium cyano- probably due to small amounts of HBr in the TMSBr rea-
borohydride to produce the benzyloxyamines 11a–e in 91– gent.
96% yield. Subsequent acetylation of 11a–e with acetyl
chloride afforded 13a–e in good yield. Different methods
were investigated for the formylation of 11. Since the mixed
anhydride method was unsuccessful, compound 11a was
formylated with 2-thioxothiazolidine-3-carbaldehyde, pre-
Synthesis of Conformationally Restricted Fosmidomycin and
FR900098 Analogues
pared by reaction between 2-mercaptothiazoline and formic
The approach used to convert the cinnamaldehydes 7c–e
acid using DCC as coupling agent. A drawback of this ap- to the corresponding α-substituted fosmidomycin deriva-
proach was the long reaction time (more than 3 d at room tives was also successfully applied to the preparation of four
temperature). Consequently, 11c,d,e were formylated using five-membered cyclic fosmidomycin analogues from cy-
formic acid and 1,1Ј-carbonyldiimidazole in dichlorometh- clopent-2-enone (Scheme 4). Michael addition of triethyl
ane. This method reduced the reaction time considerably.
phosphite to this cyclic α,β-unsaturated ketone gave direct
Benzyl deprotection by catalytic hydrogenation proved access to the diethyl 3-oxocyclopentylphosphonate.[17] The
tricky, especially in the formyl series, where this reaction remaining part of the synthesis involved the same transfor-
generally led to the formation of two reaction products. Af- mations as used for the α-aryl phosphonates. Separation of
ter their separation, mass spectrometry was useful in as- the diastereomeric pairs was realized after the hydro-
Scheme 3. Reagents and conditions: (a) O-benzylhydroxylamine, pyridine, EtOH, room temperature; (b) NaCNBH3, MeOH, HCl, room
temperature; (c) acetyl chloride, CH2Cl2, Et3N, 0 °C or carbonyldiimidazole, HCOOH, CH2Cl2, room temperature (or 2-thioxothiazolid-
ine-3-carbaldehyde for 12a); (d) H2, Pd/C, MeOH, room temperature; (e) TMSBr, CH2Cl2, room temperature.
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Synthesis of Fosmidomycin Analogues as Promising Antimalarials
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Scheme 4. Reagents and conditions: (a) triethyl phosphite, phenol, 100 °C; (b) O-benzylhydroxylamine, pyridine, EtOH, room tempera-
ture; (c) NaCNBH3, MeOH, HCl, room temperature; (d) acetyl chloride, CH2Cl2, Et3N, 0 °C or carbonyldiimidazole, HCOOH, CH2Cl2,
room temperature; (e) H2, Pd/C, MeOH, room temperature; (f) TMSBr, CH2Cl2, room temperature.
1
genolysis. The cis and trans isomers were assigned by H Table 1. Inhibitory activity on E. coli DXR enzyme.
NOEDIF NMR experiments: an interaction between the
Compound
IC50 [µ]
NOH group and the methyl groups of the phosphonate es-
ter was observed for cis-22 and cis-23, as opposed to the
trans isomer, where such a contact was missing. The 13C
Fosmidomycin
FR900098
trans-3
0.029
0.035
0.20
2.3
2.3
12
NMR spectra of compounds 22 further point to the pres- cis-3
trans-4
cis-4
ence of a major and a minor form, probably as a result of
restricted rotation in the hydroxamic group, with preferen-
tial formation of the syn isomer due to a likely hydrogen
bond between the NOH group and the carbonyl group.
By using the described procedures, we have synthesized
eleven analogues, allowing us to perform initial SAR stud-
ies for the α-aryl series.[11] Although these studies revealed
that the α-aryl analogues were generally weaker E. coli
DXR inhibitors than fosmidomycin, these analogues unam-
biguously surpassed the activity of fosmidomycin in in-
hibiting P. falciparum growth. Remarkably, the formyl ana-
logues 1c and 1e consistently outperformed the acetyl deriv-
atives 2c and 2e, both in the enzyme and the parasite
growth inhibition assays. Compound 1e emerged as the
most promising analogue with an IC50 value of 0.036 µ.
Amongst the fosmidomycin analogues in which the C–
C–C spacer is part of a cyclopentane ring, the trans ana-
logues proved notably more active than the cis isomers
(Table 1). This is in agreement with recent results obtained
with cyclopropane fosmidomycin analogues, where a trans
orientation of the phosphonate group and the hy-
droxyamide moiety also yielded the most potent inhibi-
tor.[15] Remarkably, in the cyclopentane series, the inhibi-
tory activity of the formyl analogues surpassed that of the
acetyl derivatives, while the opposite trend was observed in
the cyclopropane series.
Conclusion
In conclusion, a synthetic procedure for the preparation
of α-aryl-substituted fosmidomycin analogues was devel-
oped starting from a ring substituted benzylphosphonate.
Alternatively, these analogues were also accessible by a
Michael addition of triethyl phosphite to an appropriate
cinnamaldehyde. The latter method was also successfully
used to prepare a series of cyclopentyl analogues of fosmi-
domycin.
Experimental Section
General: IUPAC names were generated with Chemdraw Ultra 8.0
(Chemoffice 2004, Cambridge Soft, Cambridge, USA). Most reac-
tions were carried out under N2. Precoated Merck silica gel F254
plates and precoated Macherey–Nagel (Düren, Germany) silica gel
F254 plates were used for TLC, and spots were examined under UV
light at 254 nm and revealed by a phosphomolybdic/cerium sulfate
solution, iodine vapour or a dinitrophenol solution. Column
chromatography was performed on ICN silica gel (63–200 µ).
NMR spectra were obtained with a Varian Mercury 300 spectrome-
ter. Chemical shifts are given in parts per million (ppm), with δ
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T. Haemers, J. Wiesner, R. Busson, H. Jomaa, S. Van Calenbergh
FULL PAPER
2
3
relative to the residual solvent peak ([D6]DMSO: δ = 2.54 ppm for
OCH2CH3), 63.16 (d, JC,P = 6.6 Hz, OCH2CH3), 99.34 [d, JC,P
= 15.8 Hz, CH(OPh)2], 117.66 (arom. C), 117.68 (arom. C), 122.99
(arom. C), 123.01 (arom. C), 128.75 (d, arom. C), 129.83 (arom.
C), 129.85 (arom. C), 130.81 (d, arom. C), 131.29 (d, arom. C),
131.87 (d, arom. C), 133.01 (d, arom. C), 136.27 (d, arom. C),
155.95 (arom. C), 156.04 (arom. C) ppm. Exact mass (ESI-MS):
calculated for C25H27Cl2O5PNa [M+Na]+ 531.0871; found
531.0872.
1H and δ = 40.5 ppm for 13C, CDCl3: δ = 7.26 ppm for H and δ
1
= 77.4 ppm for 13C and [D6]acetone: δ = 2.05 ppm for H and δ =
1
29.84 and 206.26 ppm for 13C). Coupling constants are expressed
in Hz. Abbreviations used are: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad. All signals assigned to
hydroxy and to amino groups were exchangeable with D2O. Struc-
tural assignment was confirmed with COSY, DEPT, HMQC and/
or NOEDIF/NOESY if necessary. Mass spectra and exact mass
measurements were performed with a quadrupole/orthogonal-
acceleration time-of-flight (Q/oaTOF) tandem mass spectrometer
(qTof 2, Micromass, Manchester, U. K.) equipped with a standard
electrospray ionization (ESI) interface. Samples were infused in a
acetonitrile/water (1:1) mixture at 3 µL/min. Most chemicals were
obtained from Sigma–Aldrich or Acros Organics and were used
without further purification.
General Method for the Synthesis of 9a,b: To a mixture of alkene
6a or 6b (6.56 mmol) and 4-methylmorpholine N-oxide (0.92 g,
7.87 mmol) in dioxane (40 mL) was added an aqueous 1% solution
of OsO4 (99.1 mg, 0.39 mmol). After stirring with protection from
light at room temperature overnight, the starting material was com-
pletely converted according to TLC. Sodium periodate (2.24 g,
10.5 mmol) was then added in small portions. After completion of
the reaction (2 h), the mixture was diluted with ethyl acetate
(100 mL), filtered through Celite, and solids were washed with ethyl
acetate. The combined filtrates were washed with saturated aque-
ous NaCl (100 mL), dried with MgSO4, and the solvents were evap-
orated under vacuum to yield crude 9a or 9b, which were used in
the next step without further purification.
Diethyl (1-Phenylbut-3-enyl)phosphonate (6a): To a stirred solution
of 5a (12 mL, 57.4 mmol) in dry THF (100 mL) cooled to –50 to
–70 °C, was added a 1.6  solution of nBuLi (39 mL, 63.2 mmol)
in hexane under N2. After stirring at the same temperature for
15 min, allyl bromide (5 mL, 57.4 mmol) was added; 1 h after this
addition, the reaction mixture was refluxed for 2 h. After cooling
to room temperature, the reaction mixture was concentrated in
vacuo, and the resulting oil was diluted with toluene (200 mL),
washed with 10% NH4Cl (200 mL) and water (200 mL), dried with
MgSO4 and concentrated in vacuo. Purification of the residue by
flash chromatography (n-hexane/ethyl acetate, 8:2Ǟ7:3Ǟ6:4)
yielded compound 6a as a transparent oil (14.96 g, 97%). 1H NMR
(300 MHz, CDCl3): δ = 1.06 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.25
(t, J = 7.0 Hz, 3 H, OCH2CH3), 2.61–2.74 (m, 1 H, allyl CH2),
2.76–2.88 (m, 1 H, allyl CH2), 3.05 (ddd, JH,P = 22.0 Hz, J = 4.4,
11.1 Hz, 1 H, CHP), 3.62–3.75 (m, 1 H, OCH2CH3), 3.80–3.93 (m,
1 H, OCH2CH3), 3.95–4.09 (m, 2 H, OCH2CH3), 4.85–4.89 (m, 1
H, CH=CH2,cis), 4.93–5.00 (m, 1 H, CH=CH2,trans), 5.51–5.65 (m,
1 H, CH=CH2), 7.17–7.30 (m, 5 H, arom. H) ppm.13C NMR
General Method for Synthesis of 9c–e: Acetals 8c–e (5.0 mmol) were
hydrolyzed by treatment with a mixture of water (7 mL), acetone
(35 mL) and 2  HCl (8 mL). After heating to 60–70 °C for 3–4 h,
TLC analysis (ethyl acetate) confirmed that the reaction was fin-
ished. The solvents were evaporated under vacuum, and the residue
was dissolved in ethyl acetate (200 mL) and transferred to a sepa-
rating funnel, where it was washed twice with water (200 mL). The
organic layer was dried with MgSO4 and the solvents were evapo-
rated. The residue was purified by flash chromatography using
ethyl acetate as eluent to yield 9c–e as transparent oils. NMR re-
vealed, by disappearance of the CH=O signals, that 9a–e are prone
to oxidation upon storage when dissolved in CDCl3.
Diethyl [1-(3,4-Dichlorophenyl)-2-formylethyl]phosphonate (9e):
1
Yield: 1.28 g (76%). H NMR (300 MHz, CDCl3): δ = 1.11 (t, J =
3
(75 MHz, CDCl3): δ = 16.46 (d, JC,P = 5.7 Hz, OCH2CH3), 16.63
7.0 Hz, 3 H, OCH2CH3), 1.23 (t, J = 7.0 Hz, 3 H, OCH2CH3),
2.95–3.20 (m, 2 H, PCHCH2), 3.62 (ddd, JH,P = 22.7 Hz, J = 4.7,
9.7 Hz, 1 H, CHP), 3.74–3.83 (m, 1 H, OCH2CH3), 3.84–3.95 (m,
1 H, OCH2CH3), 3.96–4.07 (m, 2 H, OCH2CH3), 7.12–7.40 (m, 3
H, arom. H), 9.61–9.62 (m, 1 H, HC=O) ppm. 13C NMR (75 MHz,
3
2
(d, JC,P = 6.0 Hz, OCH2CH3), 34.26 (d, JC,P = 2.9, CH2CHP),
1
2
44.81 (d, JC,P = 137.1 Hz, CHP), 62.00 (d, JC,P = 7.2 Hz,
2
OCH2CH3), 62.77 (d, JC,P = 7.2 Hz, OCH2CH3), 117.03, 127.34,
128.62, 129.55, 135.56, 135.82 ppm. Exact mass (ESI-MS): calcu-
lated for C14H22O3P [M+H]+ 269.1306; found 269.1292.
3
CDCl3): δ = 16.54 (app. t, JC,P = 6.2 Hz, OCH2CH3), 37.20 (d,
1JC,P = 141.9 Hz, CHP), 44.09 (d, 2JC,P = 2.3 Hz, PCHCH2), 62.75
General Method for the Synthesis of 8c–e: A mixture of the appro-
priate acrylic aldehyde (6.17 mmol), triethyl phosphite (1.34 mL,
7.71 mmol) and phenol (1.54 g, 16 mmol) was heated to 100 °C.
After 24 h, TLC analysis (hexane/ethyl acetate, 6:4) indicated that
the reaction was finished, and the reaction mixture was sub-
sequently concentrated. The crude product was purified by flash
chromatography, eluting with hexane/ethyl acetate, 6:4. After con-
centration of the pure fractions, the desired acetals 8c–e were ob-
tained as slightly yellow oils.
2
2
(d, JC,P
=
7.2 Hz, OCH2CH3), 63.34 (d, JC,P
=
6.9 Hz,
3
4
OCH2CH3), 128.70 (d, JC,P = 6.3 Hz, arom. Co), 130.75 (d, JC,P
3
= 2.6 Hz, arom. Cm), 131.15 (d, JC,P = 6.9 Hz, arom. Co), 131.95
(d, 5JC,P = 3.7 Hz, arom. Cp), 132.92 (d, 4JC,P = 2.9 Hz, arom. Cm),
2
3
136.03 (d, JC,P = 7.2 Hz, arom. Ci), 198.13 (d, JC,P = 15.0 Hz,
HC=O) ppm. Exact mass (ESI-MS): calculated for C13H18Cl2O4P
[M+H]+ 339.03204; found 339.0325.
General Method for the Synthesis of 10a–e and 18: A mixture of
aldehydes 9a–e (3.86 mmol) and O-benzylhydroxylamine hydro-
chloride (0.61 g, 3.86 mmol) in pyridine/ethanol, 1:1 (14 mL) was
stirred at room temperature under nitrogen for 1.5–6 h. After the
solvent was removed by evaporation, the residue was co-evaporated
three times with toluene and subsequently purified by chromatog-
raphy on a silica gel column (n-hexane/ethyl acetate, 6:4 or
6:4Ǟ1:1) to give a mixture of benzyloxyimines 10a–e as transparent
oils.
Diethyl
[1-(3,4-Dichlorophenyl)-3,3-diphenoxypropyl]phosphonate
(8e): Yield: 2.29 g (70%). 1H NMR (300 MHz, CDCl3): δ = 1.13
(t, J = 7.0 Hz, 3 H, OCH2CH3), 1.25 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 2.43–2.57 (m, 1 H, PCHCH2), 2.70–2.82 (m, 1 H,
PCHCH2), 3.38 (ddd, JH,P = 22.7 Hz, J = 4.7, 10.3 Hz, 1 H, CHP),
3.74–3.87 (m, 1 H, OCH2CH3), 3.89–3.99 (m, 1 H, OCH2CH3),
3.99–4.12 (m, 2 H, OCH2CH3), 5.66 [dd, J = 6.8, 4.4 Hz, 1 H,
CH(OPh)2], 6.84–6.92 (m, 3 H, arom. H), 6.97–7.03 (m, 2 H, arom.
H), 7.18–7.27 (m, 6 H, arom. H), 7.37–7.45 (m, 2 H, arom. H) ppm.
Diethyl [(E)- and (Z)-3-(Benzyloxy)imino-1-(3,4-dichlorophenyl)pro-
pyl]phosphonate (10e): Yield: 1.57 g (92%) 1H NMR (300 MHz,
CDCl3): δ = 1.17 (dt, JH,P = 1.47 Hz, J = 7.0 Hz, 3 H, OCH2CH3),
1.28 (dt, JH,P = 3.2 Hz, J = 7.0 Hz, 3 H, OCH2CH3), 2.72–3.05
13C NMR (75 MHz, CDCl3): δ = 16.51 (app. t, JC,P = 5.8 Hz,
3
2
OCH2CH3), 34.61 (d, JC,P too small for detection, PCHCH2),
1
2
39.70 (d, JC,P = 139.9 Hz, CHP), 62.57 (d, JC,P = 7.2 Hz,
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Synthesis of Fosmidomycin Analogues as Promising Antimalarials
FULL PAPER
(m, 2 H, CHPCH2), 3.17–3.32 (m, 1 H, PCH), 3.81–3.90 (m, 1 H, 1 H, NH), 4.03–4.15 (m, 4 H, OCH2CH3), 4.69 (s, 1 H, CH2Ph),
OCH2CH3), 3.93–3.98 (m, 1 H, OCH2CH3), 3.99–4.10 (m, 2 H, 4.75 (s, 1 H, CH2Ph), 7.26–7.56 (m, 5 H, arom. H) ppm. 13C NMR
3
OCH2CH3), 4.97 (s, 1 H, OCH2Ph), 5.08 (s, 1 H, OCH2Ph), 6.55
(t, J = 5.3 Hz, 1 H, HC=N), 7.11–7.39 (m, 8 H, arom. H) ppm.
(75 MHz, CDCl3): δ = 16.76 (d, JC,P = 5.8 Hz, OCH2CH3), 25.27
(d, JC,P = 2.9 Hz, CH2), 25.72 (d, JC,P = 2.6 Hz, CH2), 30.18 (CH2),
Exact mass (ESI-MS): calculated for C20H25Cl2NO4P [M+H]+ 30.34 (CH2), 31.54 (d, JC,P = 2.3 Hz, CH2), 31.67 (d, JC,P = 2.1 Hz,
444.090; found 444.091.
CH2), 33.73 (d, JC,P = 147.9 Hz, CHP), 34.55 (d, JC,P = 147.4 Hz,
CHP), 61.65–62.13 (m, OCH2CH3 and NCH), 77.59 (OCH2Ph),
76.95 (OCH2Ph), 128.11 (arom. C), 128.61 (arom. C), 128.67
(arom. C), 129.57 (arom. C), 130.42; 137.86 (arom. C) ppm. Exact
mass (ESI-MS): calculated for C16H27NO4P [M+H]+ 328.1678;
found 328.1660.
Diethyl {3-[(Benzyloxy)imino]cyclopentyl}phosphonate (18): Yield:
3.07 g (90%). 1H NMR (300 MHz, CDCl3): δ = 1.30 (t, J = 7.0 Hz,
3 H, OCH2CH3), 1.31 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.80–2.89
(m, 7 H, C5H7P), 4.04–4.15 (m, 4 H, OCH2CH3), 5.06 (s, 2 H,
CH2Ph), 7.26–7.34 (m, 5 H, arom. H) ppm. 13C NMR (75 MHz,
3
Formylation of Compounds 11 and 19
CDCl3): δ = 16.74 (d, JC,P = 5.8 Hz, OCH2CH3), 25.68 (d, JC,P
2.6 Hz, CH2), 26.03 (d, JC,P = 3.2 Hz, CH2), 27.92 (d, JC,P
12.1 Hz, CH2), 29.19 (d, JC,P = 1.7 Hz, CH2), 30.91 (d, JC,P
11.5 Hz, CH2), 32.07 (d, JC,P = 1.4 Hz, CH2), 34.77 (d, JC,P
=
=
=
=
Method A: Formic acid (1 equiv.) and 2-mercaptothiazoline
(1 equiv.) were dissolved in CH2Cl2 (0.5 ), cooled to 0 °C and
DCC (1 equiv.) was added in one portion. After the reaction mix-
ture was filtered and concentrated, the residue was purified by
chromatography (CH2Cl2) to afford 2-thioxothiazolidine-3-carbal-
dehyde as a yellow solid.
151.4 Hz, CHP), 34.99 (d, JC,P = 151.7 Hz, CHP), 62.06 (m,
OCH2CH3), 75.92 (OCH2Ph), 75.95 (OCH2Ph), 127.93 (arom. C),
127.95 (arom. C), 128.16 (arom. C), 128.18 (arom. C), 128.56
(arom. C), 128.55 (arom. C), 138.26 (arom. C), 138.33 (arom. C),
164.12 (d, 3JC,P = 13.8 Hz, C=N), 164.33 (d, 3JC,P = 15.0 Hz, C=N)
ppm. 31P NMR (120 MHz, CDCl3): δ = 32.12, 32.36 ppm. Exact
mass (ESI-MS): calculated for C16H25NO4P [M+H]+ 326.1521;
found 326.1523.
Diethyl {3-[N-(Benzyloxy)formamido]-1-phenylpropyl}phosphonate
(12a): 2-Thioxothiazolidine-3-carbaldehyde (1 equiv.) was dissolved
in CH2Cl2 and added to a solution of 11a (1 equiv.) in CH2Cl2
(0.1 ). The reaction mixture was stirred for 3 d. The reaction mix-
ture was extracted with water, dried with MgSO4 and concentrated
in vacuo. The residue was purified by flash chromatography
(CH2Cl2/MeOH, 95:5) to yield 12a in 89% yield. 1H NMR
(300 MHz, CDCl3): δ = 1.07 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.26
(t, J = 7.0 Hz, 3 H, OCH2CH3), 2.17 (m, 1 H, CH2CHP), 2.45–2.48
(m, 1 H, CH2CHP), 3.06 (ddd, JH,P = 23.0 Hz, J = 4.1, 11.1 Hz, 1
H, CHP), 3.39 (m, 1 H, CH2N), 3.50 (m, 1 H, CH2N), 3.62–3.75
(m, 1 H, OCH2CH3), 3.81–3.91 (m, 1 H, OCH2CH3), 3.97–4.10 (m,
2 H, OCH2CH3), 4.74 and 4.94 (2×br. s, 2 H, PhCH2O), 7.26–7.35
(m, 10 H, arom. H), 8.16 (br. s, 1 H, HC=O) ppm. 13C NMR
General Procedure for the Reduction of the O-Benzyloximes 10a–e
to 11a–e and 18 to 19: Sodium cyanoborohydride (12.95 mmol,
0.81 g) was added to
a solution of O-benzyloximes 10a–e
(2.59 mmol) in methanol (15 mL). Two drops of methyl orange in-
dicator were added followed by dropwise addition of concentrated
hydrochloric acid, until the solution remained pink and milky for
at least 0.5 h. The reaction mixture was stirred at room temperature
for 3–16 h, and the solvent was removed under vacuum. The resi-
due was taken up in CH2Cl2 (100 mL) and washed until alkaline
with 1  potassium hydroxide solution, and the aqueous portion
extracted with CH2Cl2 (3×100 mL). The combined organic ex-
tracts were dried with MgSO4, filtered and the solvent was re-
moved. The residue was purified on a silica gel column and eluted
with CH2Cl2/MeOH, 95:5 or n-hexane/ethyl acetate, 4:6. After con-
centration of the appropriate fractions, O-benzyloxyamines 11a–e
and 19 were obtained as clear oils.
3
(75 MHz, CDCl3): δ = 16.40 (d, JC,P = 5.7 Hz, OCH2CH3), 16.58
3
1
(d, JC,P = 6.0 Hz, OCH2CH3), 27.42 (m, CH2CHP), 40 (d, JC,P
2
= 140 Hz, CHP), 43.11 (m, NCH2), 62.19 (d, JC,P = 7.2 Hz,
OCH2CH3), 63.96 (d, JC,P
2
= 7.2 Hz, OCH2CH3), 77.42
(OCH2Ph), 127.77 (arom. C), 128.91 (arom. C), 129.26 (arom. C),
129.47 (arom. C), 129.56 (arom. C), 129.63 (arom. C), 131.10
(arom. C), 135.09 (arom. C), 163.32 (m, HC=O) ppm. Mass (ESI-
MS): calculated for C21H29NO5P [M+H]+ 406.1783; found 406.1.
Diethyl
[3-(Benzyloxyamino)-1-(3,4-dichlorophenyl)propyl]phos-
phonate (11e): Yield: 1.05 g (91%). 1H NMR (300 MHz, CDCl3):
δ = 1.16 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.28 (t, J = 7.0 Hz, 3
H, OCH2CH3), 1.97–2.13 (m, 1 H, CH2CHP), 2.28–2.42 (m, 1 H,
CH2CHP), 2.64–2.74 (m, 1 H, CH2N), 2.85–2.93 (m, 1 H, CH2N),
3.20 (ddd, JH,P = 22.6 Hz, J = 4.1, 11.1 Hz, 1 H, CHP), 3.77–3.89
(m, 1 H, OCH2CH3), 3.91–3.99 (m, 1 H, OCH2CH3), 3.99–4.13 (m,
2 H, OCH2CH3), 4.61–4.70 (m, 2 H, PhCH2O), 7.13–7.17 (m, 1 H,
arom. H), 7.26–7.40 (m, 7 H, arom. H) ppm. 13C NMR (75 MHz,
Method B: To a three-neck flask containing a solution of formic
acid (0.61 mmol, 30 µL) in CH2Cl2 (0.6 mL) was added 1,1Ј-car-
bonyldiimidazole (0.64 mmol, 0.10 g). After 20 min, benzyloxyam-
ines 11c,e (0.61 mmol) were dissolved in CH2Cl2 (1 mL) and then
transferred to the three-neck flask. After 5 h, the mixture was parti-
tioned between water (70 mL) and CH2Cl2 (70 mL). The water
layer was extracted twice with CH2Cl2 (70 mL). The combined or-
ganic layers were dried with MgSO4 and concentrated in vacuo,
and the residue was purified by flash chromatography (n-pentane/
acetone, 6:4) to give 12c,e as transparent oils.
3
3
CDCl3): δ = 16.56 (d, JC,P = 7.8 Hz, OCH2CH3), 16.64 (d, JC,P
2
= 8.1 Hz, OCH2CH3), 27.73 (d, JC,P = 2.9 Hz, CH2CHP), 41.35
1
3
(d, JC,P = 139.6 Hz, CHP), 49.48 (d, JC,P = 15.3 Hz, NCH2),
Diethyl {3-[N-(Benzyloxy)formamido]-1-(3,4-dichlorophenyl)propyl}-
phosphonate (12e): Yield: 245 mg (85%). 1H NMR (300 MHz,
CDCl3): δ = 1.14 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.27 (t, J =
7.0 Hz, 3 H, OCH2CH3), 2.07–2.21 (m, 1 H, CH2CHP), 2.37–2.51
(m, 1 H, CH2CHP), 3.00 (ddd, JH,P = 23.0 Hz, J = 4.1, 11.4 Hz, 1
H, CHP), 3.23–3.38 (m, 1 H, CH2N), 3.44–3.46 (m, 1 H, CH2N),
3.78–3.88 (m, 1 H, OCH2CH3), 3.89–3.99 (m, 1 H, OCH2CH3),
3.99–4.11 (m, 2 H, OCH2CH3), 4.75 and 4.91 (2×br. s, 2 H,
PhCH2O), 7.12–7.40 (m, 8 H, arom. H), 8.16 (br. s, 1 H, HC=O)
2
2
62.36 (d, JC,P = 6.9 Hz, OCH2CH3), 62.88 (d, JC,P = 6.9 Hz,
OCH2CH3), 77.88 (OCH2Ph), 128.13 (arom. C), 128.61 (arom. C),
128.63 (arom. C), 128.87 (d, JC,P = 6.6 Hz, arom. C), 130.65 (d,
JC,P = 2.6 Hz, arom. C), 131.42 (d, JC,P = 6.9 Hz, arom. C), 131.53
(arom. C), 132.74 (d, JC,P = 2.9 Hz, arom. C), 136.73 (d, JC,P
=
6.9 Hz, arom. C), 137.88 (arom. C) ppm. Exact mass (ESI-MS):
calculated for C20H27Cl2NO4P [M+H]+ 446.1055; found 446.1060.
Diethyl [3-(Benzyloxyamino)cyclopentyl]phosphonate (19): Yield:
1.83 g, mixture of cis and trans (80%). 1H NMR (300 MHz,
CDCl3): δ = 1.30 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.30 (t, J = OCH2CH3), 16.61 (d, JC,P = 6.1 Hz, OCH2CH3), 27.34 (m,
3
ppm. 13C NMR (75 MHz, CDCl3): δ = 16.50 (d, JC,P = 6.1 Hz,
3
1
7.0 Hz, 3 H, OCH2CH3), 1.42–2.40 (m, 8 H, C5H8P), 3.58–3.69 (m,
CH2CHP), 41.46 (d, JC,P = 138.48 Hz, CHP), 42.50 (m, NCH2),
Eur. J. Org. Chem. 2006, 3856–3863
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3861

T. Haemers, J. Wiesner, R. Busson, H. Jomaa, S. Van Calenbergh
FULL PAPER
2
2
62.59 (d, JC,P = 7.2 Hz, OCH2CH3), 63.09 (d, JC,P = 6.9 Hz, (OCH2CH3), 62.15 (OCH2CH3), 156.49 (C=O, major), 162.37
OCH2CH3), 78.29 (OCH2Ph), 128.86 (arom. C), 128.95 (arom. C), (C=O, minor) ppm. Exact mass (ESI-MS): calculated for
129.94 (arom. C), 129.69 (arom. C), 130.81 (arom. C), 131.24
(arom. C), 131.92 (arom. C), 132.93 (arom. C), 134.27 (arom. C),
135.87 (arom. C), 163.32 (m, HC=O) ppm. Exact mass (ESI-MS):
calculated for C21H27Cl2NO5P [M+H]+ 474.1004; found 474.1000.
C10H21NO5P [M+H]+ 266.1158; found 266.1131.
Diethyl [3-(N-Hydroxyformamido)cyclopentyl]phosphonate (trans-
1
22): Yield: 170 mg (35%). H NMR (300 MHz, CDCl3): δ = 1.18
(t, J = 7.0 Hz, 3 H, OCH2CH3), 1.18 (t, J = 6.8 Hz, 3 H,
OCH2CH3), 1.75–2.08 (m, 7 H, C5H7P), 3.95 (m, 4 H, OCH2CH3),
4.68 (s, 1 H, CHNOH), 7.80 (s, 1 H, HC=O, minor), 8.17 (s, 1 H,
HC=O, major), 9.78 (br. s, 1 H, NOH) ppm. 13C NMR (75 MHz,
Diethyl {3-[N-(Benzyloxy)formamido]cyclopentyl}phosphonate (20):
Yield: 1.3 g, mixture of cis and trans (97%). H NMR (300 MHz,
1
CDCl3): δ = 1.23 (m, 6 H, OCH2CH3), 1.64–2.39 (m, 7 H, C5H7P),
3.98–4.09 (m, 4 H, OCH2CH3), 4.4 (m, 1 H, CHN), 4.90 (br. s, 2
H, OCH2Ph), 7.30–7.32 (m, 5 H, arom. H), 8.10 and 8.13 (2×s, 1
3
CDCl3): δ = 16.60 (d, JC,P = 5.5 Hz, OCH2CH3), 25.25 (CH2),
28.08 (d, JC,P = 10.4 Hz, CH2, major), 28.83 (d, JC,P = 11.2 Hz,
H, HC=O) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.76 (d, JC,P
3
CH2, minor), 29.4 (s, CH2, major), 30.07 (CH2, minor), 33.41 (d,
1
1JC,P = 148.3 Hz, CHP, major), 34.22 (d, JC,P = 150.0 Hz, CHP,
= 5.8 Hz, 2 C, OCH2CH3), 24.40 (d, JC,P = 2.0 Hz, CH2), 25.60
3
3
1
minor), 55.44 (d, JC,P = 15.8 Hz, CHN, major), 60.50 (d, JC,P
=
(CH2), 29.98 (d, JC,P = 7.8 Hz, CH2), 33.31 (d, JC,P = 150.6 Hz,
1
18.1 Hz, CHN, minor), 62.10–62.47 (m, 2C, OCH2CH3), 156.43
(C=O, minor), 162.48 (C=O, major) ppm. Exact mass (ESI-MS):
calculated for C10H21NO5P [M+H]+ 266.1158; found 266.1143.
CHP), 33.66 (d, JC,P = 149.7 Hz, CHP), 57.73 (m, CHN), 59.03
(m, CHN), 62.01 (m, OCH2CH3), 79.50 (m, OCH2Ph), 128.95–
129.63 (3 arom. C), 134.72 (arom. C), 165.10 (m, HC=O) ppm.
Exact mass (ESI-MS): calculated for C17H27NO5P [M+H]+
356.1627; found 356.1629.
General Method for the Phosphonate Deprotection: Esters 14, 15,
22 or 23 (0.84 mmol) were dissolved in CH2Cl2 (10 mL) and treated
dropwise with TMSBr (3.36 mmol, 0.50 g) under N2. The reaction
mixture was stirred at room temperature for 2 h. After completion
of the reaction, the volatile compounds were removed in vacuo to
give the corresponding phosphonic acids in almost quantitative
yield. All final compounds were purified using a preparative HPLC
General Method for the Benzyl Deprotection of 12, 13, 20 and 21:
A solution of compounds 12 and 13 or 20 and 21 (0.9 mmol) in
MeOH (8 mL) was hydrogenated at atmospheric pressure in the
presence of Pd (10 wt.-% on activated carbon, 40 mg). After stir-
ring for 5 h, the reaction mixture was filtered through a Celite pad.
The solvent was removed under vacuum, and the crude mixture
was purified by column chromatography on silica gel (CH2Cl2/
MeOH, 95:5).
system on
a
C18 column (5 µm; Phenomenex; Luna;
250×21.2 mm) with a linear gradient of acetonitrile (0Ǟ100%) in
5 m NH4OAc solution at a flow rate of 17.5 mL/min over 20 min.
The purity of all target compounds was assessed by analytical
HPLC [5 µm; Phenomenex; C18(2), 250×4.6 mm] using the same
gradient at a flow rate of 1 mL/min. All final compounds were
obtained as hygroscopic powders after lyophilisation. All powders
were white, except the five-membered cyclic analogues which were
obtained as orange powders.
Diethyl
[1-(3,4-Dichlorophenyl)-3-(N-hydroxyformamido)propyl]-
phosphonate (14e): Yield: 157 mg (57%). 1H NMR (300 MHz,
CDCl3): δ = 1.09–1.24 (m, 6 H, OCH2CH3), 2.11 (m, 1 H,
CH2CHP), 2.46 (m, 1 H, CH2CHP), 3.01–3.17 (m, 1 H, CHP),
3.22–3.35 (m, 1 H, CH2N), 3.45–3.56 (m, 1 H, CH2N), 3.77–4.04
(m, 4 H, OCH2CH3), 7.08–7.11 (m, 1 H, arom. H), 7.32–7.37 (m,
2 H, arom. H), 7.55 (br. s, 1 H, HC=O), 8.24 (s, 1 H, NOH) ppm.
[1-(3,4-Dichlorophenyl)-3-(N-hydroxyformamido)propyl]phosphonic
Acid (1e): 1H NMR (300 MHz, D2O): δ = 1.93–2.15 (m, 1 H, β-
CH), 2.24–2.38 (m, 1 H, β-CH), 2.73–2.87 (m, 1 H, α-CH), 3.17–
3.47 (m, 2 H, γ-CH2), 7.07–7.12 (m, 1 H, arom. H), 7.33–7.39 (m,
2 H, arom. H), 7.44 and 8.07 (2×s, 1 H, HC=O) ppm. 13C NMR
13C NMR (75 MHz, CDCl3): δ = 16.48 (app. t, JC,P = 5.8 Hz,
3
OCH2CH3), 26.90 (CH2CHP, major), 27.08 (CH2CHP, minor),
40.09 (d, 1JC,P = 139.3 Hz, CHP, major), 40.96 (d, 1JC,P = 139.3 Hz,
3
CHP, minor), 44.60 (d, JC,P = 15.8 Hz, NCH2, minor), 47.45 (d,
1
3JC,P
=
15.0 Hz, NCH2, major), 62.84 (d, JC,P
=
6.9 Hz,
2
(75 MHz, D2O): δ = 26.49 (s, β-CH2), 42.82 (d, JC,P = 129.6 Hz,
2
α-CH), 48.86 (d, 3JC,P = 17.0 Hz, γ-CH2), 128.92 (d, JC,P = 5.8 Hz,
OCH2CH3, major), 63.01 (d, JC,P = 7.2 Hz, OCH2CH3, minor),
2
2
arom. C), 130.04 (d, JC,P = 3.8 Hz, arom. C), 130.55 (d, JC,P =
63.24 (d, JC,P = 6.9 Hz, OCH2CH3, major), 63.32 (d, JC,P
=
2.6 Hz, arom. C), 130.73 (d, JC,P = 6.0 Hz, arom. C), 131.88 (d,
JC,P = 3.2 Hz, arom. C), 138.80 (d, JC,P = 7.2 Hz, arom. C), 159.70
(C=O, major) and 163.76 (C=O, minor) ppm. 31P NMR (121 MHz,
D2O): δ = 21.46, 21.78 (major and minor isomers) ppm. Exact mass
(ESI-MS): calculated for C10H11Cl2NO5P [M–H]– 325.9751; found
325.9745.
6.1 Hz, OCH2CH3, minor), 128.81 (d, JC,P = 6.3 Hz, arom. C,
major), 128.95 (d, JC,P = 6.9 Hz, arom. C, minor), 130.69 (arom.
C, minor), 130.91 (arom. C, major), 131.14 (d, JC,P = 6.9 Hz, arom.
C, major), 131.24 (d, JC,P = 9.2 Hz, arom. C, minor), 131.74 (d,
JC,P = 3.8 Hz, arom. C, minor), 131.98 (d, JC,P = 3.8 Hz, arom. C,
major), 132.70 (d, JC,P = 2.6 Hz, arom. C, minor), 133.01 (d, JC,P
= 2.6 Hz, arom. C, major), 135.60 (d, JC,P = 7.2 Hz, arom. C,
major), 136.00 (d, JC,P = 7.5 Hz, arom. C, minor), 157.37 (C=O,
major), 163.03 (C=O, minor) ppm. Exact mass (ESI-MS): calcu-
lated for C14H21Cl2NO5P [M+H]+ 384.0535; found 384.0530.
[(1R,3R)-3-(N-Hydroxyformamido)cyclopentyl]phosphonic Acid and
[(1S,3S)-3-(N-Hydroxyformamido)cyclopentyl]phosphonic
Acid
(trans-3): 1H NMR (300 MHz, D2O): δ = 1.73–2.04 (m, 7 H, α-CH
and CH2), 4.13 (br. s, 1 H, NCH), 7.84, 8.07 (2×s, 1 H, major and
minor HC=O) ppm. 13C NMR (75 MHz, D2O): δ = 25.55 (d, JC,P
= 1.2 Hz, CH2), 28.56 (d, JC,P = 10.4 Hz, CH2), 31.10 (s, CH2),
35.94 (d, 1JC,P = 141.7 Hz, α-CH), 61.46 (d, JC,P = 17.3 Hz, NCH),
159.23 (C=O) ppm. 31P NMR (121 MHz, D2O): δ = 27.71, 27.91
(major and minor isomers) ppm. Exact mass (ESI-MS): calculated
for C6H11NO5P [M–H]– 208.0374; found 208.0366.
Diethyl [3-(N-Hydroxyformamido)cyclopentyl]phosphonate (cis-22):
1
Yield: 90 mg (19%). H NMR (300 MHz, CDCl3): δ = 1.26 (m, 6
H, OCH2CH3), 1.75–2.42 (m, 7 H, C5H7P), 4.03–4.22 (m, 4 H,
OCH2CH3), 4.83 (s, 1 H, CHNOH), 7.88 (s, 1 H, HC=O), 8.25 (s,
1 H, HC=O), 9.70 (s, 1 H, NOH) ppm. 13C NMR (75 MHz,
3
CDCl3): δ = 16.65 (d, JC,P = 5.8 Hz, OCH2CH3), 26.15 (CH2,
major), 26.66 (CH2, minor), 29.21 (d, JC,P = 12.7 Hz, CH2, minor),
29.81 (d, JC,P = 11.5 Hz, CH2, major), 29.81 (CH2, minor), 30.44
[(1R,3S)-3-(N-Hydroxyformamido)cyclopentyl]phosphonic Acid and
[(1S,3R)-3-(N-Hydroxyformamido)cyclopentyl]phosphonic Acid (cis-
3): H NMR (300 MHz, D2O): δ = 1.49–2.17 (m, 7 H, α-CH and
1
1
(CH2, major), 33,54 (d, JC,P = 148.3 Hz, CHP, major), 35,51 (d,
3
1JC,P = 148.9 Hz, CHP, minor), 55.08 (d, JC,P = 12.7 Hz, CHN,
CH2), 4.21 (br. m, 1 H, NCH), 7.88, 8.09 (2×s, 1 H, major and
3
major), 60.19 (d, JC,P
= 11.5 Hz, CHN, minor), 62.05
minor HC=O) ppm. 13C NMR (75 MHz, D2O): δ = 26.73 (d, JC,P
3862
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3856–3863

Synthesis of Fosmidomycin Analogues as Promising Antimalarials
FULL PAPER
Lichtenthaler, D. Soldati, E. Beck, Science 1999, 285, 1573–
1576.
[7] M. Courtois, Z. Mincheva, F. Andreu, M. Rideau, M. C.
Viaud-Massuard, J. Enzyme Inhib. Med. Chem. 2004, 19, 559–
565.
[8] R. Ortmann, J. Wiesner, A. Reichenberg, D. Henschker, E.
Beck, H. Jomaa, M. Schlitzer, Arch. Pharm. 2005, 338, 305–
314.
[9] R. Ortmann, J. Wiesner, A. Reichenberg, D. Henschker, E.
Beck, H. Jomaa, M. Schlitzer, Bioorg. Med. Chem. Lett. 2003,
13, 2163–2166.
= 1.1 Hz, CH2), 29.89 (d, JC,P = 11.2 Hz, CH2), 30.76 (CH2), 36.47
1
(d, JC,P = 141.5 Hz, α-CH), 61.36 (d, JC,P = 10.9 Hz, NCH),
159.11 (C=O) ppm. 31P NMR (121 MHz, D2O): δ = 27.74 ppm.
Exact mass (ESI-MS): calculated for C6H11NO5P [M–H]–
208.0374; found 208.0378.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details (1H, 13C, 31P NMR, MS) for intermedi-
ates (6b, 7d–e, 8c–d, 9c–d, 10a–d, 11a–d, 12c, 13a–e, 14c, 15a–e, 17,
21, trans-23, cis-23) and final products (1c, 2a–e, trans-4, cis-4).
[10]
[11]
[12]
A. Reichenberg, J. Wiesner, C. Weidemeyer, E. Dreiseidler, S.
Sanderbrand, B. Altincicek, E. Beck, M. Schlitzer, H. Jomaa,
Bioorg. Med. Chem. Lett. 2001, 11, 833–835.
T. Haemers, J. Wiesner, S. Van Poecke, J. L. Goeman, H.
Jomaa, S. Van Calenbergh, Bioorg. Med. Chem. Lett. 2006, 16,
1888–1891.
Acknowledgments
This work was supported by grants from the European Commis-
sion (QLK2-CT-2002-00887) and INTAS (03-51-4077).
a) J. G. Topliss, J. Med. Chem. 1972, 15, 1006–1011; b) J. G.
Topliss, J. Med. Chem. 1977, 20, 463–469.
[1] 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–
738.
[13] a) S. C. Fields, Tetrahedron 1999, 55, 12237–12273; b) D. En-
ders, A. Saint-Dizier, M.-I. Lannou, A. Lenzen, Eur. J. Org.
Chem. 2006, 29–49.
[2] M. A. Missinou, S. Borrmann, A. Schindler, S. Issifou, A. A.
Adegnika, P. B. Matsiegui, R. Binder, B. Lell, J. Wiesner, T.
Baranek, H. Jomaa, P. G. Kremsner, Lancet 2002, 360, 1941–
1942.
[3] J. Zeidler, J. Schwender, C. Muller, J. Wiesner, C. Weidemeyer,
E. Beck, H. Jomaa, Z. Naturforsch., Teil C 1998, 53, 980–986.
[4] T. Kuzuyama, T. Shimizu, S. Takahashi, H. Seto, Tetrahedron
Lett. 1998, 39, 7913–7916.
[14] K. Hemmi, H. Takeno, M. Hashimoto, T. Kamiya, Chem.
Pharm. Bull. 1982, 30, 111.
[15] V. Devreux, J. Wiesner, J. L. Goeman, J. Van der Eycken, H.
Jomaa, S. Van Calenbergh J. Med. Chem. 2006, 49, 2656–2660.
[16] W. Flitsch, W. Lubisch, J. Rosche, Liebigs Ann. Chem. 1987, 8,
661–664.
[17] R. G. Harvey, Tetrahedron 1966, 22, 2561–2573.
[18] G. Battistuzzi, S. Cacchi, G. Fabrizi, Org. Lett. 2003, 5, 777–
780.
[5] M. Rohmer, Nat. Prod. Rep. 1999, 16, 565–574.
[6] H. Jomaa, J. Wiesner, S. Sanderbrand, B. Altincicek, C. Weide-
meyer, M. Hintz, I. Turbachova, M. Eberl, J. Zeidler, H. K.
Received: March 7, 2006
Published Online: July 5, 2006
Eur. J. Org. Chem. 2006, 3856–3863
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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