Functionalized phosphanyl-phosphonic acids as unusual complexing units as analogues of fosmidomycin

Article abstract of DOI:10.1002/ejoc.201200210

Fosmidomycin (1a) and FR-90098 are potent inhibitors of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), the second enzyme of the non-mevalonate (MEP) pathway responsible for the biosynthesis of isoprenoids. This paper describes the synthesis of four types of targets bearing a phosphanyl-phosphonic acid motif as the common core for the inhibition of DXR. In these structures, the hydroxamic acid was replaced by various chelators based on a phosphinic acid linked to different functional groups capable of forming five- or six-membered chelating rings. Copyright

Full text of DOI:10.1002/ejoc.201200210

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
FULL PAPER
DOI: 10.1002/ejoc.201200210
Functionalized Phosphanyl-Phosphonic Acids as Unusual Complexing Units as
Analogues of Fosmidomycin
Sonia Montel,[a] Camille Midrier,[a] Jean-Noël Volle,[a] Ralf Braun,[b] Klaus Haaf,[b]
Lothar Willms,[b] Jean-Luc Pirat,[a] and David Virieux*[a]
Dedicated to Professor Henri-Jean Cristau on the occasion of his 70th birthday
Keywords: Synthetic methods / Natural products / Enzymes / Inhibitors / Phosphorus / Palladium / Arylation
Fosmidomycin (1a) and FR-90098 are potent inhibitors of 1-
deoxy- -xylulose-5-phosphate reductoisomerase (DXR), the
second enzyme of the non-mevalonate (MEP) pathway re-
sponsible for the biosynthesis of isoprenoids. This paper de-
scribes the synthesis of four types of targets bearing a phos-
phanyl-phosphonic acid motif as the common core for the
inhibition of DXR. In these structures, the hydroxamic acid
was replaced by various chelators based on a phosphinic acid
linked to different functional groups capable of forming five-
or six-membered chelating rings.
D
(NADPH), generally embedded in the active site. Although
X-ray crystal structures of the complex of DXR with fosmi-
domycin have been solved, the rational design of new po-
tent inhibitors by docking methods is obviously compli-
cated, because DXR undergoes a dramatic conformational
change induced by the inclusion of the substrate or fosmi-
domycin. In addition, the latter is known as a slow-binding
inhibitor, and the ternary complexes constituted by DXR,
NADPH, and fosmidomycin in the early stage or in the
tight-binding mode deeply differ from each other.[4]
Introduction
The non-mevalonate pathway is an alternative metabolic
pathway leading to the formation of isopentenyl pyrophos-
phate and is widely found in higher plants, protozoa, and
bacteria, but, interestingly, there is no equivalent pathway
in mammals. Identifying a non-mevalonate pathway inhibi-
tor would greatly contribute to the search for safer antibiot-
ics, antimalarials, and, for our interests, herbicides.[1] The
unique properties of 1-deoxy-d-xylulose-5-phosphate re-
ductoisomerase (DXR), the central enzyme of the non-mev-
alonate pathway, make it a remarkable and attractive target
for drug design. Fosmidomycin (1a), a phosphonohy-
droxamic acid isolated from Streptomyces lavendulae, acts
as an inhibitor of DXR and still remains, along with its N-
acetyl homologue FR90098 (1b), one of the most potent
inhibitors ever known.[2] The X-ray diffraction analyses of
the co-crystals of DXR and fosmidomycin and DXR and
deoxyxylulose phosphate (DXP, 2) show that the phos-
phonic or phosphate group interacts with a highly specific
and polar pocket in the enzyme site, allowing only few
structural modifications (Figure 1).[3] In contrast, the cat-
ion-complexing unit represented by the hydroxamic acid of-
fers fine-tuning possibilities for the complexation abilities
as well as potential secondary interactions with the cofactor
Figure 1. X-ray crystal structure of DXR active site with fosmido-
mycin (1a) or DXP (2) and NADPH.
Phosphinic acids are often employed as complexing units
particularly in the inhibition of matrix metalloproteinases
(MMPs), a family of zinc-dependent endoproteinases.[5] Of
the many published inhibitors of DXR, a large majority
contain the hydroxamic acid functionality which is already
present in fosmidomycin, resulting in less effort toward
other classes of inhibitors. From a structural point of view,
[a] Institut Charles Gerhardt, UMR 5253, AM2N, ENSCM,
8, Rue de l’Ecole Normale, 34296 Montpellier, France
Fax: +33-4-67144319
E-mail: david.virieux@enscm.fr
[b] Bayer CropScience AG, Chemistry Frankfurt, G 836,
Industriepark Höchst,
65926 Frankfurt am Main, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200210.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
D. Virieux et al.
FULL PAPER
Figure 2. Modified chelators 3–6, analogues of fosmidomycin (1a), docked in the active site of DXR.
the tetrahedral geometry of the phosphinic acid group on a multigram scale from cheap and commercially avail-
could directly mimic the tetrahedral alcohol function of able reagents. Indeed, 7a and 7b were considered as key
DXP (2). As a consequence, phosphinate-based inhibitors precursors to introduce chemical diversity by exploiting the
may possess useful properties, derived from their better outstanding reactivity associated with the P–H bond.
complexation capabilities associated with the presence of a
O-Benzyl phosphonophosphinate 7a was obtained by the
side chain that can bind in other specific pockets of the esterification of dry hypophosphorous acid with benzyl
enzyme.[6] In accordance with this feature, the presence of alcohol in refluxing chloroform (Scheme 1).[8] Then, a pal-
other heteroatoms would lead to original chelators through ladium-catalyzed hydrophosphinylation was performed
the formation of potential five- or six-membered chelating with Pd/C and Xanthphos as the ligand to afford 7a in 66%
rings (Figure 2).[7] Similarly, the modulations of the hard- overall yield.[9] The O-ethyl phosphinate 7b was synthesized
ness and softness parameters and the hybridization of these from ammonium hypophosphite (10) by radical addition to
heteroatoms would allow modifications in the complexing diethyl allylphosphonate (9), mediated by triethylborane
abilities. For these purposes, four types of targets (i.e. 3–6) and oxygen.[10] The resulting acid 11 was then transformed
were designed (see Figure 2) to explore the molecular diver- into the corresponding ester 7b in 59% overall yield using
sity and structurally embedded rigid or flexible chelating triethyl orthoformate in refluxing chloroform.
unit.
α-Hydroxy and α-Amino Phosphanylphosphonic Acids 3a–d
Results and Discussion
Starting from the two precursors 7a and 7b, the molecu-
lar diversity was then introduced by introducing an α-sub-
stituted hydroxy- or aminomethyl group to the reactive H-
phosphinate function. Although the target structures 3 pre-
All of the target structures were synthesized from the 3- sented some similarities, the chemical behavior of the alde-
phosphinoylpropylphosphonates 7a (R = Bn) or 7b (R = hyde and imine reagents were quite different and required
Et), versatile building blocks, which were readily available specific reaction conditions (Scheme 2).
Syntheses of the Diethyl (3-Alkoxyphosphinoylpropyl)-
phosphinate Precursors 7a and 7b
Scheme 1. Synthesis of phosphanyl-H-phosphinates 7a and 7b.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
Fosmidomycin Analogues
direct basic activation (with cesium carbonate, sodium hy-
dride, and potassium tert-butoxide) as well as the formation
of the silylphosphonite by reaction of 7b with trimethylsilyl
chloride were attempted, but the best yields were obtained
by using 4-(dimethylamino)pyridine (DMAP) in refluxing
dichloroethane. The cleavage of both the phosphonic and
phosphinic ester moieties mediated by trimethylsilyl brom-
ide then resulted in the formation of the deprotected car-
bamoylphosphanylphosphonic acids 4a–d in quantitative
yields.
Scheme 3. Synthesis of Carbamoylphosphanylphosphonic acids
4a–d.
Scheme 2. α-Hydroxy and α-amino phosphanylphosphonic acids
3a–d.
Aryl and Heteroarylphosphinoylphosphonic Acids 5 and 6
Metal-cation chelation is an important feature recog-
nized in the development of new biologically active mole-
cules.[15] In this context, the heterocyclic core of some com-
plexing agents have demonstrated their efficiency, particu-
larly in chelation therapy of iron by siderophores.[16] In this
context, Arbusov and Michaelis–Becker reactions provide
easy and useful procedures to form carbon–phosphorus
bonds, but these methods are not directly applicable to the
formation of sp2-hybridized aromatic carbon atoms, even if
a direct SNAr process is presumed. As originally illustrated
by Hirao et al., one of the best approaches is the palladium-
catalyzed arylation of P–H reagents using aryl halides, pref-
erentially an aryl bromide or iodide.[17] A striking detail
specific to this method is the full regioselectivity of the aryl-
ation, that is, the P–C bond formation takes place exclu-
sively at the position initially occupied by the bromide or
iodide on the arylating agent, and a full retention of config-
uration at the phosphorus center is jointly observed during
the transformation of the P–H bond into a P–Ar bond.[18]
Three different aldehydes (formaldehyde, acetaldehyde,
and benzaldehyde) were used to introduce the α-hydroxy
group. Formaldehyde was thermally depolymerized from
the paraformaldehyde, and upon heating to reflux for 1 h,
the reaction resulted in complete consumption of the start-
ing material.[11] The pure product was obtained in a modest
crude NMR yield of 56% and was finally isolated in a 16%
yield after two successive flash chromatography purifica-
tions, which were necessary because of the product’s po-
larity. For acetaldehyde, the Texier–Boullet et al. methodol-
ogy, which uses preadsorbed potassium fluoride on alumina
as a base, was preferentially applied and gave the expected
product in 20% yield.[12] For benzaldehyde, silyl-Abramov
conditions were advantageously used to obtain the expected
structure. Hydrogenolysis of the O-benzyl phosphinate was
achieved using hydrogen and a Pd/C catalyst. Finally, hy-
drolysis of both phosphinic and phosphonic esters was ef-
fective under acidic conditions affording 3a–c, respectively,
in low overall yields. The α-aminobenzyl derivative 3d was
synthesized in a 14% overall yield in two steps from 7b
by the addition of the corresponding imine and then full
deprotection using hydrobromic acid.
Using Pd(PPh3)4
Because the palladium(0) catalyst is involved in such cou-
pling reactions, we first used a catalytic amount of tetrakis-
(triphenylphosphane)palladium in the presence of triethyl-
amine. The experimental results are listed in Table 1. Ac-
Carbamoylphosphanylphosphonic Acids 4a–d
α-Ketophosphinates are scarcely described in the litera- cording to the literature, when bromobenzene was used, the
ture, but they are proven to be useful chelating agents. For 31P NMR yields (Table 1, Entry 2) were efficient as ex-
example, they inhibit human calpain I, a calcium-dependent pected. However, the O-benzyl-protected phosphinate 7a
cysteine protease.[13] Carbamoylphosphinates 4a–d were (Table 1, Entry 1) gave arylphosphinate 12a (Ar = Ph), and
synthesized by the condensation of phosphono-H-phosphin- concomitantly a small percentage of 7a underwent debenz-
ate 7b with various isocyanates (Scheme 3).[14] Different ylation, which was confirmed by the presence of benzyl
conditions were established for the optimization of this re- alcohol in GC–MS. Different solvents were also tried. In
action using phenyl isocyanate as the reactant. Both the general, ethanol resulting in better conversions, but lower
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
D. Virieux et al.
FULL PAPER
Table 1. Palladium(0)-catalyzed arylation of 7a and 7b.
Ar–X[a]
Conditions
Conversion (31P NMR yield)
12a-Bn
12a-Et
12a-Et
13a
Ph–Br
Ph–Br
Ph–I
7a, 3% “Pd”, PhMe, reflux, 4 d
100% (32%)
97% (72%)
29% (16%)
76% (4%)
74% (–)
7b, 10% “Pd”, EtOH, 80 °C, 14 h
7b, 10% “Pd”, EtOH, 80 °C, 14 h
7b, 10% “Pd”, THF/EtOH, 10:1, reflux, 8 h
7b, 30% “Pd”, PhMe/EtOH, 2:1, reflux, 14 h
7b, 30% “Pd”, PhMe, reflux, 3 h
2-bromopyridine
5-bromo-1-methyl-1H-imidazole
2-bromothiazole
13b
13c
64% (–)
[a] Ar–X (1.5 equiv.) was used.
31P NMR yields, because of the formation of tetraethyl phenylphosphane with bidentate ligands in the catalytic sys-
propyl-1,3-diphosphonate. Its formation could be attrib- tem.[20] This system exhibited a higher efficiency than
uted either to oxidation and esterification steps or to a Pd(PPh3)4 partly because of better reductive elimination
likely attack by the ethanol on the phosphorus atom of the given its bidentate character. Gratifyingly, the conditions
Ar–Pd–P intermediate complex.
developed for the use of dppf and Pd2dba3 permitted the
The phosphinylation of heterocycles were problematic, successful formation of 2-pyridyl, 2-pyrimidinyl, and 2-[4-
because a target could not be isolated when 2-bromopyr- (trifluoromethyl)pyridyl] derivatives in yields ranging from
idine, 2-bromothiazole, or 2-bromoimidazole were used. 66 to 74% (Table 3). To the best of our knowledge, this is
The complexation abilities of the resulting heteroarylphos- the first cross-coupling reaction between an H-phosphinate
phinates or precursor 7b could induce this lack of reactivity. and heteroaryl chlorides.[21] To confirm the mechanism of
the coupling, a palladium-free reaction was performed giv-
ing no conversion of 7b, excluding a direct SNAr process.
Using PdCl2
Then, 2-bromothiophene and 2-bromothiazole were con-
verted successfully into 13d and 13c, respectively, in 50%
and 65% isolated yields. The coupling of the 5-(1-methyl-
1H-imidazolyl) derivative gave 13b in 84% for the 31P NMR
yield. Unfortunately, 13b was unstable during flash
chromatography. To circumvent this problem, the purifica-
tion of 13b was conducted by trituration and multiple ex-
tractions, which resulted in this low yield.
Another method involving a palladium(II) complex as
the precursor was tried, as such air-stable complexes are
generally easier to handle. In the literature, the PdII com-
plex is reduced in situ to Pd0 by treatment with triethylsil-
ane under an inert atmosphere.[19] However, in many exam-
ples, ligands such as phosphanes can behave as reducing
agents. After optimization of the conditions with bromo-
benzene as the model reagent, four of the protected aryl-
phosphinates 12a–d were obtained in isolated yields ranging
from 51% to 62% (Table 2).
Table 3. Palladium(II)- and dppf-catalyzed arylation of 7b.
Heteroaryl halide
Time[a] Yield (31P NMR yield)
13a 2-bromopyridine
13b 5-bromo-1-methyl-1H-imidazole
13c 2-bromothiazole
13d 2-bromothiophene
13e 2-chloropyrimidine
14 h
14 h
15 h
15 h
7 h
74% (96%)
30% (84%)
65% (84%)
50% (80%)
68% (80%)
66% (88%)
Table 2. Palladium(II)-catalyzed arylation of 7b.
Ar–X[a]
31P NMR yield
Yield
12a-Et
12b
Ph–Br
75%
70%
81%
78%
20%
5%
62%
54%
61%
51%
–
13f 2-chloro-4-trifluoromethylpyridine
3 h
2-AcOC6H4Br
2-MeOC6H4Br
2-AcHNC6H4Br
2-bromopyridine
2-bromothiophene
12c
[a] Pd2dba3 (5 mol-%), dppf (10 mol-%), NEt3 (3 equiv.), PhMe,
80 °C.
12d
13a
13d
–
[a] Ar–X (1.5 equiv.) and PdCl2 (10 mol-%) were used.
Deprotection
The deprotection of phosphanyl-phosphinic esters 12a–d
and 13a–f was performed using refluxing HCl (6 n) or
TMSBr (trimethylsilyl bromide) in dichloromethane at
Using Pd2dba3
On the basis of these insights, specific conditions were room temperature followed by methanolysis.[22] 2-Acetyl de-
developed to enable the cross-coupling step with heteroaryl rivative 12b and 2-anilinyl derivative 12d were deprotected
halides. The efficiency in the formation of the 2-pyridyl- using trimethylsilyl bromide to afford phosphanyl-phos-
phosphonates was increased by the replacement of tri- phonic triacids 5b and 5d, respectively, along with the O-
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
Fosmidomycin Analogues
and N-acetyl-protected compounds (Table 4). The pro- eroaryl chlorides were successfully applied to a fosmidomy-
portion of the deprotected phenol or amine depended on cin-related structure, clearly broadening the scope and use-
the use of water or methanol in the solvolysis reaction. fulness of this reaction.
Acetyl groups were fully removed using a solution of HCl
Living systems in nature are complex, therefore, all of
(1 n) in methanol. When pyrimidinylphosphinate 13e and the fosmidomycin analogues were tested directly on dif-
thiazolylphosphinate 13c were subjected to the deprotection ferent weed plants in a greenhouse using a specific formula-
conditions, both TMSBr and HCl quantitatively unexpec- tion by Bayer CropScience for highly polar compounds. In
tedly led to the formation of the propane-1,3-diphosphonic such conditions, no significant in vivo activity was ob-
acid.[23] Under acidic conditions, a possible protonation of served.
the heterocycle would induce the nucleophilic attack of
water on the phosphorus atom, and consequently cleave the
phosphorus–carbon bond.
Experimental Section
Table 4. Deprotection of aryl and heteroaryl phosphinates 12 and
General Methods: All of the reactions were performed under a ni-
13.
trogen atmosphere unless otherwise stated. Unless specified, all of
the reagents and starting materials were purchased from commer-
cial sources and used as received. The solvents were distilled prior
to use. Analytical thin layer chromatography (TLC) was performed
using precoated plates of silica gel 60F254, and the visualizations
were achieved by UV light (254 nm) or by treatment with a phos-
phomolybdic acid or permanganate solution as developing agents
followed by heating. Purifications by flash chromatography were
Ar or Het
Conditions
Yield
performed with silica gel (60 Å, 35–70 μm) or prepacked columns
(from 12 to 120 g scale) of silica (35–70 μm). 1H NMR spectro-
scopic data were recorded at 400 or 250 MHz. 13C NMR spectro-
scopic data were recorded at 100 or 62.5 MHz, and 31P NMR spec-
troscopic data were recorded at 162 or 101 MHz. The chemical
shifts are reported in ppm, and the coupling constants (J) are re-
ported in Hz. The chemical shift values are referenced against the
residual proton in the deuterated solvents. In the 13C NMR spectra,
signals corresponding to C, CH, CH2, or CH3 were assigned from
the JMOD sequence. The multiplicities are given as s (singlet), d
(doublet), t (triplet), q (quadruplet), and m (multiplet). Low and
high resolution mass spectra were recorded with a time-of-flight
mass spectrometer using electrospray ionization (ESI), with H3PO4
(0.1% in water/acetonitrile, 1:1) as the internal reference.
5b
5d
6a
6c
6d
6e
6f
2-AcOC6H4
2-AcHNC6H4
2-pyridyl
2-thiazolyl
2-thienyl
2-pyrimidinyl
2-(4-trifluoromethyl)pyridyl
B[a]
89%
90%
95%
–
87%
–
B[b]
B
A or B
B
A or B
B
91%
[a] The crude reaction mixture issued from B contained a 3:2 ratio
of O-acetyl derivative 12b and 12b. [b] The crude reaction mixture
issued from B contained a 2:1 ratio of N-acetyl derivative 12d and
12d.
Lithium bromide was used for the cleavage of the ester
functions to obtain the free phosphinic acids from 2-thiaz-
olylphosphinate 13c and 2-pyrimidinylphosphinate 13e
(Scheme 4). Heating of 13c and 13e in acetonitrile at reflux
with LiBr gave the expected lithium salts 14c and 14e in
95% and 93% yields, respectively.
Benzyl Hypophosphite (8): Into
a 50-mL three-necked flask
equipped with a heavy solvent extractor and condenser were intro-
duced dry hypophosphorous acid (2.0 g, 0.03 mol), chloroform
(30 mL), and benzyl alcohol (12.5 mL, 0.12 mol). The reaction
mixture was heated at reflux for 14 h. After cooling, the benzene
was removed by concentration under vacuum using a distillation
apparatus and keeping the temperature below 30 °C. A mixture of
benzyl hypophosphite and benzyl alcohol was obtained quantita-
tively as a colorless liquid and used directly without further purifi-
cation. 31P NMR (161.97 MHz, CDCl3): δ = 12.37 (s) ppm. 1H
3
NMR (400.13 MHz, CDCl3): δ = 4.94 (d, JH,P = 10.6 Hz, 2 H),
1
6.95 (d, JH,P = 564.6 Hz, 2 H), 7.04–7.21 (m, 5 H) ppm.
Scheme 4. Nucleophilic deprotection of phosphinates 13c and 13e.
Ammonium Hypophosphite (10): Into a 3-L Erlenmeyer flask was
introduced aqueous hypophosphorus acid (50 wt.-%/wt., 100 g,
0.76 mol), and the mixture was cooled in an ice bath and stirred.
Then, an aqueous solution of ammonia (28%, 60 mL, 0.88 mol)
was slowly added. After the complete addition, the reaction mix-
ture was stirred for 20 min at room temperature. Acetone (2 L) was
poured into the reaction mixture, and the resulting white solid was
filtered and washed with acetone (300 mL). The salt was then dried
under vacuum to afford ammonium hypophosphite (61.8 g, 83%)
as a white solid which was stored in a Schlenk tube under nitrogen.
Conclusions
In summary, the syntheses of four new families of fosmi-
domycin analogues were accomplished using triethyl (3-
phosphanylpropyl)phosphonate (7b) as a central scaffold.
Owing to the presence of the P–H bond, a divergent pro-
cedure introduced chemical diversity into the cation-com-
plexing subunit of fosmidomycin (1a) to afford original che-
lating functionalities. Interestingly, the palladium-catalyzed
31P NMR (101.25 MHz, CDCl3): δ = 7.83 (s) ppm. 31P NMR
1
with coupling 1H (101.25 MHz, CDCl3): δ = 7.83 (t, JP,H
=
couplings of heteroaryl halides and, particularly, some het- 518.5 Hz) ppm.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
D. Virieux et al.
FULL PAPER
4
4
Diethyl Allylphosphonate (9): Into a 250-mL two-necked flask
equipped with a condenser were introduced triethyl phosphite
(80 mL, 0.48 mol) and allyl bromide (60 mL, 0.72 mol). The reac-
tion mixture was stirred for 14 h at 160 °C, and then it was distilled
under reduced pressure (82–85 °C, 2 Torr) to yield a colorless liquid
(78.8 g, 92%). 31P NMR (161.97 MHz, CDCl3): δ = 27.7 (s) ppm.
(101.25 MHz, CDCl3): δ = 26.45 (d, JP,P = 3.7 Hz), 33.22 (d, JP,P
1
3
= 3.7 Hz) ppm. H NMR (400.13 MHz, CDCl3): δ = 1.28 (t, JH,H
3
= 7.0 Hz, 6 H), 1.32 (t, JH,H = 7.2 Hz, 3 H), 1.77–1.92 (m, 6 H),
4.00–4.18 (m, 6 H), 7.06 (d, 1JH,P = 531.8 Hz, 1 H) ppm. 13C NMR
3
(100.61 MHz, CDCl3): δ = 14.5 (m), 16.2 (d, JC,P = 5.9 Hz), 16.4
3
1
3
(d, JC,P = 5.9 Hz), 26.1 (dd, JC,P = 142.0 Hz, JC,P = 14.6 Hz),
3
1
3
2
1H NMR (400.13 MHz, CDCl3): δ = 1.34 (t, JH,H = 7.0 Hz, 6 H),
29.07 (dd, JC,P = 93.7 Hz, JC,P = 14.6 Hz), 61.7 (d, JC,P =
2
3
4
2
2.64 (m, JH,P = 21.9 Hz, JH,H = 7.4 Hz, JH,H = 1.2 Hz, 2 H),
6.6 Hz), 62.6 (d, JC,P = 6.6 Hz) ppm. HRMS (ESI): calcd. for
4.06–4.20 (m, 4 H), 5.12–5.35 (m, 2 H), 5.70–5.92 (m, 1 H) ppm. C9H23O5P2 273.1021; found 273.1007.
13C NMR (100.61 MHz, CDCl3): δ = 16.2 (d, 3JC,P = 6.0 Hz), 31.5
3-[Hydroxy(hydroxymethyl)phosphinoyl]propylphosphonic Acid (3a)
1
2
3
(d, JC,P = 139.0 Hz), 61.7 (d, JC,P = 6.7 Hz), 119.5 (d, JC,P
14.5 Hz), 127.3 (d, JC,P = 11.2 Hz) ppm.
=
2
Diethyl 3-[Benzyloxy(hydroxymethyl)phosphinoyl]propylphosphon-
ate: Into a 50-mL two-necked flask under nitrogen were introduced
7a (4.0 g, 11.9 mmol), dry toluene (20 mL), triethylamine (166 μL,
1.19 mmol), and paraformaldehyde (0.72 g, 23.9 mmol). The reac-
tion mixture was heated at reflux. After completely dissolving the
paraformaldehyde, the reaction was heated for 1 h. After cooling
and concentration, the crude residue was dissolved in chloroform
(100 mL), and the resulting mixture was washed with water
(2ϫ10 mL). The organic phase was dried with MgSO4 and then
concentrated. The resulting residue was purified twice by column
chromatography on silica gel (EtOAc/EtOH, from 100:0 to 70:30)
to give the product (0.70 g, 16%) as a yellow oil. 31P NMR
(101.25 MHz, CDCl3): δ = 30.80 (d, 4JP,P = 3.95 Hz), 54.31 (d, 4JP,P
= 3.95 Hz) ppm. 1H NMR (400.13 MHz, CDCl3): δ = 1.22 (t, 3JH,H
= 7.0 Hz, 6 H), 1.72–1.95 (m, 6 H), 3.71–3.96 (m, 2 H), 4.93–4.02
(m, 4 H), 4.94–5.04 (m, 2 H), 7.23–7.32 (m, 5 H) ppm. 13C NMR
(100.61 MHz, CDCl3): δ = 15.1 (dd, 2JC,P = 4.4 Hz, 2JC,P = 2.9 Hz),
Diethyl 3-(Benzyloxy-H-phosphinoyl)propylphosphonate (7a): Into a
500-mL three-necked flask equipped with a condenser were added
acetonitrile (125 mL), palladium on charcoal (10%, 883 mg,
0.83 mmol), and Xantphos (526 mg, 0.907 mmol). The resulting
mixture was stirred at room temperature for 10 min. A solution of
alkyl hypophosphorus ester (249 mmol) and diethyl allylphos-
phonate 9 (14.7 g, 82.5 mmol) in acetonitrile (125 mL) was added.
The reaction was heated at reflux for 18 h and then was filtered
through Celite at room temperature. After concentration under
vacuum, the benzyl alcohol was removed under reduced pressure.
The residue was purified by column chromatography on silica gel
(EtOAc/EtOH, from 100:0 to 70:30) to yield a yellow oil (18.2 g,
4
66%). 31P NMR (161.97 MHz, CDCl3): δ = 30.17 (d, JP,P
=
4.0 Hz), 37.16 (d, JP,P = 4.0 Hz) ppm. 1H NMR (400.13 MHz,
4
CDCl3): δ = 1.33 (t, 3JH,H = 7.1 Hz, 3 H), 1.82–2.02 (m, 6 H), 4.06–
1
4.12 (m, 4 H), 5.03–5.31 (m, 2 H), 7.15 (d, JH,P = 534.9 Hz, 1 H)
3
1
3
16.4 (d, JC,P = 6.6 Hz), 26.1 (dd, JC,P = 88.55 Hz, JC,P
=
7.37–7.41 (m, 5 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 14.6
1
3
14.63 Hz), 26.2 (dd, JC,P = 140.51 Hz, JC,P = 13.2 Hz), 58.3 (d,
1JC,P = 105.38 Hz), 61.7 (d, 2JC,P = 6.6 Hz), 66.2 (d, 2JC,P = 5.8 Hz),
127.9 (s), 128.6 (s), 128.4 (s), 136.4 (d, 3JC,P = 5.1 Hz) ppm. HRMS
(ESI): calcd. for C15H27O6P2 365.1283; found 365.1296.
2
2
3
(dd, JC,P = 4.4 Hz, JC,P = 2.2 Hz), 16.4 (d, JC,P = 5.8 Hz), 26.2
1
3
1
(dd, JC,P = 141.3 Hz, JC,P = 15.4 Hz), 28.3 (dd, JC,P = 92.2 Hz,
3JC,P = 13.9 Hz), 61.7 (d, JC,P = 6.6 Hz), 67.8 (d, JC,P = 6.6 Hz),
128.7–128.1 (m, 4 C) ppm. HRMS (ESI): calcd. for C14H25O5P2
335.1177; found 335.1155.
2
2
Diethyl 3-[Hydroxy(hydroxymethyl)phosphinoyl]propylphosphonate:
Into a Schlenk tube under nitrogen were introduced 10% Pd/C
(60 mg) and diethyl 3-[benzyloxy(hydroxymethyl)phosphinoyl]-
propylphosphonate (600 mg, 1.64 mmol) in EtOH (40 mL). The re-
action mixture was vigorously stirred at room temp. for 12 h under
a hydrogen atmosphere (1 atm). Then, the Pd/C was filtered
through Celite, and the EtOH was removed under vacuum to yield
Ammonium 3-(Diethoxyphosphonyl)propyl-H-phosphinate (11): Into
a 1-L open flask were introduced ammonium hypophosphite
(20.7 g, 0.25 mol), diethyl allylphosphonate (17.8 g, 0.1 mol), and
methanol (490 mL). After complete dissolution of the salts, trieth-
ylborane (1 m solution in tetrahydrofuran, 20 mL, 0.02 mol) was
added slowly. The resulting mixture was stirred vigorously for 4 h.
After concentration under vacuum, the resulting crude mixture was
dried under high vacuum to remove the traces of methanol, and
then chloroform (250 mL) was added. The mixture was stirred in
a sonic bath for 30 min. A white suspension formed and was fil-
tered. The resulting filtrate was concentrated and dried to yield 11
(25.0 g, quantitative) as a colorless oil. 31P NMR (161.97 MHz,
the product (0.43 g, 95%) as
a
colorless oil. 31P NMR
4
(161.97 MHz, CDCl3): δ = 31.45 (d, JP,P = 4.0 Hz), 50.18 (br.
s) ppm. 1H NMR (400.13 MHz, CDCl3): δ = 1.26 (t, JH,H
=
3
7.1 Hz, 6 H), 1.78–1.95 (m, 6 H), 3.70–3.95 (m, 2 H), 3.97–4.07 (m,
4 H), 7.73 (br. s, 2 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ =
3
3
15.07 (s), 16.4 (d, JC,P = 5.9 Hz), 26.1 (dd, 1JC,P = 140.5 Hz, JC,P
1
3
= 13.2 Hz), 26.5 (dd, JC,P = 87.8 Hz, JC,P = 18.3 Hz), 59.1 (d,
4
CDCl3): δ = 26.58 (s), 31.52 (d, JP,P = 3.96 Hz) ppm. 1H NMR
1JC,P = 106.1 Hz), 61.8 (d, JC,P = 6.6 Hz) ppm. HRMS (ESI):
2
3
(400.13 MHz, CDCl3): δ = 1.25 (t, JH,H = 7.1 Hz, 6 H), 1.57–1.98
calcd. for C8H21O6P2 275.0813; found 275.0784.
1
(m, 6 H), 3.98–4.05 (m, 4 H), 6.93 (d, JH,P = 506.3 Hz, 1 H), 7.73
3-[Hydroxy(hydroxymethyl)phosphinoyl]propylphosphonic Acid (3a):
Into a 25-mL two-necked flask equipped with a condenser were
introduced, respectively, diethyl 3-[hydroxy-(hydroxymethyl)phos-
phinoyl]propylphosphonate (0.36 g, 1.32 mmol), water (2 mL), and
hydrochloric acid (35% solution, 4.8 mL). The reaction mixture
was heated at reflux for 4 h and then concentrated under vacuum.
Compound 3a (280 mg, 97%) was obtained without further purifi-
cation as a white foam. 31P NMR (161.97 MHz, D2O): δ = 29.57
2
(s, 4 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 15.2 (d, JC,P
= 4.3 Hz), 16.4 (d, 3JC,P = 6.6 Hz), 26.0 (dd, 1JC,P = 140.5 Hz, 3JC,P
1
3
= 14.6 Hz), 31.9 (dd, JC,P = 91.5 Hz, JC,P = 14.6 Hz), 61.7 (d,
2JC,P = 6.6 Hz) ppm. HRMS (ESI): calcd. for C7H19O5P2 245.0708;
found 245.0731.
Diethyl 3-(Ethoxy-H-phosphinoyl)propylphosphonate (7b): Into a
500-mL two-necked flask equipped with a condenser were intro-
duced, under nitrogen, 11 (25 g, 0.095 mol), chloroform (250 mL),
and triethyl orthoformate (31.6 mL, 0.190 mol). The resulting mix-
ture was heated at reflux for 13 h. After concentration under vac-
uum, the resulting crude mixture was purified by column
chromatography on silica gel (EtOAc/EtOH, from 100:0 to 70:30)
4
4
(d, JP,P = 5.9 Hz), 50.97 (d, JP,P = 5.9 Hz) ppm. 1H NMR
2
(400.13 MHz, D2O): δ = 1.72–1.85 (m, 6 H), 3.70 (d, JH,P
=
5.0 Hz, 2 H) ppm. 13C NMR (100.61 MHz, D2O): δ = 14.9 (t, 2JC,P
1
3
= 3.7 Hz), 26.1 (dd, JC,P = 88.6 Hz, JC,P = 16.1 Hz,), 27.2 (dd,
1JC,P = 133.9 Hz, JC,P = 14.6 Hz), 57.8 (d, 1JC,P = 108.3 Hz) ppm.
3
to give 7b (15.2 g, 59%) as
a
colorless liquid. 31P NMR
HRMS (ESI): calcd. for C4H13O6P2 219.0187; found 219.0212.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
Fosmidomycin Analogues
4
3-[Hydroxy(1-hydroxyethyl)phosphinoyl]propylphosphonic Acid (3b)
stereomer A): δ = 30.80 (d, JP,P = 5.4 Hz, 50%), 50.35 (br. s,
50%) ppm. 31P NMR (161.97 MHz, CDCl3, diastereomer B): δ =
Diethyl 3-[Ethoxy(1-hydroxyethyl)phosphinoyl]propylphosphonate:
Into a 25-mL two-necked flask under nitrogen was introduced 7b
(4.0 g, 14.7 mmol). The starting material was stirred in an ice bath,
and then acetaldehyde (1.67 mL, 29.4 mmol) was added. Potassium
fluoride preabsorbed on alumina (6.8 g, 58.8 mmol, 1:1, w/w) was
added in portions, and the resulting mixture was vigorously stirred
at room temp. for 5 h. Dichloromethane (50 mL) was added, and
then the reaction mixture was stirred for 30 min. The mixture was
filtered through Celite to remove the solid. The filtrate was concen-
trated, and the residue was purified twice by column chromatog-
raphy on silica gel (EtOAc/EtOH, from 100:0 to 70:30) to yield the
product (0.90 g, 20%) as a colorless oil. 31P NMR (161.97 MHz,
4
1
30.91 (d, JP,P = 5.0 Hz, 50%), 52.60 (br. s, 50%) ppm. H NMR
3
(400.13 MHz, CDCl3): δ = 1.12 (t, JH,H = 7.1 Hz, 3 H), 1.20 (t,
3JH,H = 7.1 Hz, 6 H), 1.62–1.79 (m, 6 H), 3.73–4.01 (m, 6 H), 4.85
2
2
(d, JH,P = 7.7 Hz, 0.5 H, diastereomer), 4.93 (d, JH,P = 8.7 Hz,
0.5 H, diastereomer), 7.20–7.40 (m,
(100.61 MHz, CDCl3): δ = 14.9–15.1 (m), 16.4 (d, JC,P = 5.9 Hz),
16.6 (d, JC,P = 5.8 Hz), 16.6 (d, JC,P = 5.8 Hz), 25.1 (dd, JC,P
5
H) ppm. 13C NMR
3
3
3
1
=
=
3
1
3
88.5 Hz, JC,P = 14.6 Hz), 25.6 (dd, JC,P = 88.5 Hz, JC,P
1
3
15.4 Hz), 26.3 (dd, JC,P = 140.5 Hz, JC,P = 13.2 Hz), 25.1 (dd,
1JC,P = 140.5 Hz, JC,P = 13.2 Hz), 61.4–61.7 (m), 71.8 (d, JC,P
=
3
1
1
4
103.2 Hz), 72.2 (d, JC,P = 102.5 Hz), 126.5 (d, JC,P = 5.1 Hz),
4
5
5
127.1 (d, JC,P = 5.1 Hz), 127.8 (d, JC,P = 2.2 Hz), 128.0 (d, JC,P
= 2.2 Hz), 128.2 (d, 5JC,P = 2.2 Hz), 128.3 (d, 5JC,P = 2.2 Hz), 136.8
(s) ppm. HRMS (ESI): calcd. for C16H29O6P2 379.1439; found
379.1423.
4
CDCl3, diastereomer A): δ = 30.89 (d, JP,P = 4.0 Hz, 38%), 53.48
(br. s, 38%) ppm. 31P NMR (161.97 MHz, CDCl3, diastereomer
4
1
B): δ = 31.03 (d, JP,P = 4.0 Hz, 62%), 54.20 (br. s, 62%) ppm. H
3
NMR (400.13 MHz, CDCl3): δ = 1.26 (t, JH,H = 7.1 Hz, 9 H),
1.35 (dd, 3JH,P = 13.4 Hz, 3JH,H = 7.3 Hz, diastereomer B) and 1.37
3-[Hydroxy(hydroxybenzyl)phosphinoyl]propylphosphonic Acid (3c):
Into a 25-mL two-necked flask equipped with a condenser were
introduced, respectively, diethyl 3-[ethoxy(hydroxybenzyl)phos-
phinoyl]propylphosphonate (0.50 g, 1.33 mmol), water (2 mL), and
hydrochloric acid (35% solution, 4.8 mL). The reaction mixture
was heated at reflux for 5 h and then concentrated under vacuum.
The crude residue was purified by precipitation from a mixture of
methanol and chloroform (1 mL/10 mL). The resulting solid was
filtered and washed with chloroform to afford 3c (250 mg, 64%) as
(dd, 3JH,P = 15.1 Hz, JH,H = 7.1 Hz, diastereomer A) (3 H), 1.78–
3
2.04 (m, 6 H), 3.87–3.95 (m, 1 H), 3.98–4.08 (m, 6 H) ppm. 13C
2
NMR (100.61 MHz, CDCl3): δ = 15.1 (t, JC,P = 3.7 Hz, dia-
stereomer B), 15.3 (t, JC,P = 3.7 Hz, diastereomer A), 16.4–16.8
(m), 24.8 (dd, JC,P = 85.6 Hz, JC,P = 14.6 Hz, diastereomer A),
25.3 (dd, JC,P = 85.3 Hz, JC,P = 14.6 Hz, diastereomer B), 26.3
2
1
3
1
3
1
3
(dd, JC,P = 140.5 Hz, JC,P = 13.2 Hz, diastereomer A), 26.4 (dd,
3
1JC,P = 141.2 Hz, JC,P = 13.9 Hz, diastereomer B), 61.0–61.7 (m),
2
2
a yellow foam. 31P NMR (161.97 MHz, D2O): δ = 29.20 (d, JP,P
= 5.9 Hz), 48.65 (d, JP,P = 5.9 Hz) ppm. H NMR (400.13 MHz,
4
64.7 (d, JC,P = 7.6 Hz, diastereomer A), 64.7 (d, JC,P = 8.3 Hz,
diastereomer B) ppm. HRMS (ESI): calcd. for C11H27O6P2
317.1283; found 317.1256.
4
1
3
D2O): δ = 1.70–1.95 (m, 6 H), 4.89 (d, JH,H = 7.8 Hz, 1 H), 7.21–
7.31 (m, 5 H) ppm. 13C NMR (100.61 MHz, D2O): δ = 15.0 (t,
3-[Hydroxy(1-hydroxyethyl)phosphinoyl]propylphosphonic Acid (3b):
Into a 25-mL two-necked flask equipped with a condenser were
introduced, respectively, diethyl 3-[ethoxy(1-hydroxyethyl)phos-
phinoyl]propylphosphonate (0.79 g, 2.5 mmol), water (2 mL), and
hydrochloric acid (35% solution, 4.8 mL). The reaction mixture
was heated at reflux for 5 h and then was concentrated under vac-
uum. Compound 3b (0.55 g, 95%) was obtained without further
purification as a white foam. 31P NMR (161.97 MHz, D2O): δ =
2JC,P = 4.4 Hz), 25.5 (dd, JC,P = 87.8 Hz, JC,P = 16.1 Hz), 27.4
1
3
1
3
1
(dd, JC,P = 133.9 Hz, JC,P = 14.6 Hz), 71.7 (d, JC,P = 107.6 Hz),
127.0 (d, JC,P = 5.1 Hz), 128.4 (d, JC,P = 2.9 Hz), 128.6 (d, JC,P
= 2.2 Hz), 136.0 (d, JC,P = 1.5 Hz) ppm. HRMS (ESI): calcd. for
C10H17O6P2 295.0500; found 295.0513.
3-[Hydroxy(aminobenzyl)phosphinoyl]propylphosphonic Acid Hydro-
bromide (3d)
4
4
1
32.31 (d, JP,P = 5.9 Hz), 56.22 (d, JP,P = 5.9 Hz) ppm. H NMR
(400.13 MHz, D2O): δ = 1.24 (dd, 3JH,P = 15.7 Hz, 3JH,H = 7.2 Hz,
Diethyl 3-[Ethoxy(diphenylmethylaminobenzyl)phosphinoyl]propyl-
phosphonate: Into a 50-mL three-necked flask equipped with a con-
denser were dissolved, under nitrogen, 7b (1 g, 3.67 mmol) and N-
benzylidene-1,1-diphenylmethanamine (2.17 g, 8.04 mmol) in anhy-
drous EtOH (20 mL). The reaction mixture was heated at reflux
for 15 d. After cooling and filtration, the reaction mixture was con-
centrated under vacuum. Purification of the resulting residue was
performed by column chromatography on silica gel (EtOAc/EtOH,
from 100:0 to 95:05) to yield the product (0.61 g, 31%) as a yellow
oil. 31P NMR (161.97 MHz, CDCl3, diastereomer A): δ = 30.66 (d,
4JP,P = 5.9 Hz, 53%), 51.17 (d, 4JP,P = 5.9 Hz, 53%) ppm. 31P NMR
(161.97 MHz, CDCl3, diastereomer B): δ = 30.85 (d, 4JP,P = 5.9 Hz,
47%), 50.68 (d, 4JP,P = 5.9 Hz, 47%) ppm. 1H NMR (400.13 MHz,
CDCl3): δ = 1.18–1.27 (m, 9 H), 1.54–2.06 (m, 6 H), 3.16–3.22 and
3 H), 1.70–1.85 (m, 6 H), 3.90 (qd, 3JH,H = 7.2 Hz, JH,P = 1.5 Hz,
2
1 H) ppm. 13C NMR (100.61 MHz, D2O): δ = 14.6 (t, JC,P
=
2
1
3
4.4 Hz), 14.96 (s), 24.8 (dd, JC,P = 86.4 Hz, JC,P = 16.4 Hz), 27.1
(dd, JC,P
1
3
1
= 134.7 Hz, JC,P = 14.6 Hz), 64.2 (d, JC,P =
111.2 Hz) ppm. HRMS (ESI): calcd. for C5H15O6P2 233.0344;
found 233.0367.
3-[Hydroxy(hydroxybenzyl)phosphinoyl]propylphosphonic Acid (3c)
Diethyl 3-[Ethoxy(hydroxybenzyl)phosphinoyl]propylphosphonate:
Into a 5-mL two-necked flask under nitrogen was introduced 7b
(1.0 g, 3.67 mmol). The mixture was stirred in an ice bath, and then
trimethylsilyl chloride (1.3 mL, 9.91 mmol) was added dropwise.
The resulting mixture was stirred at 0 °C for 1 h. Benzaldehyde
(779 mg, 7.34 mmol) was added, and then the reaction was stirred
for an additional 1 h at 0 °C. Dichloromethane (2 mL) was then
added, and the reaction was stirred at room temperature for 20 h.
Extraction between acetonitrile (100 mL) and hexane (2ϫ100 mL)
was performed and the acetonitrile layer was concentrated. The
crude residue was dissolved in chloroform (100 mL), and the re-
sulting mixture was extracted with water (2ϫ5 mL). The organic
phase was dried with MgSO4 and concentrated under vacuum. The
residue was purified by column chromatography on silica gel
(EtOAc/EtOH, from 100:0 to 70:30) to yield the product (0.25 g,
18%) as a colorless oil. 31P NMR (161.97 MHz, CDCl3, dia-
2
2
3.61–3.68 (m, 1 H), 3.62 (d, JH,P = 15.4 Hz) and 3.74 (d, JH,P
=
16.2 Hz, 1 H), 3.85–4.40 (m, 5 H), 4.10 (s, 1 H), 7.10–7.38 (m, 15
H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 15.1 (t, JC,P
=
=
=
2
2
1
4.4 Hz), 15.5 (t, JC,P = 4.4 Hz), 16.3–16.9 (m), 26.4 (dd, JC,P
3
1
3
140.5 Hz, JC,P = 13.9 Hz), 26.6 (dd, JC,P = 140.5 Hz, JC,P
13.9 Hz), 27.0 (dd, 1JC,P = 92.9 Hz, 3JC,P = 15.4 Hz), 27.6 (dd, 1JC,P
3
1
= 92.2 Hz, JC,P = 16.1 Hz), 59.7 (d, JC,P = 101.7 Hz), 60.1 (d,
1JC,P = 98.8 Hz), 61.2–62.1 (m, JC,P = 7.32 Hz, JC,P = 6.6 Hz),
2
2
3
3
63.6 (d, JC,P = 4.4 Hz), 63.8 (d, JC,P = 2.9 Hz), 127.0–128.9 (m),
135.3 (d, JC,P = 3.7 Hz), 135.5 (s), 141.8, 142.0, 143.6, 143.7 ppm.
HRMS (ESI): calcd. for C29H40NO5P2 544.2382; found 544.2364.
2
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
D. Virieux et al.
FULL PAPER
3-[Hydroxy(aminobenzyl)phosphinoyl]propylphosphonic Acid Hydro-
bromide (3d): Into a 25-mL two-necked flask equipped with a con-
denser were introduced, respectively, diethyl 3-[ethoxy(diphenylme-
= 146.4 Hz) ppm. HRMS (ESI): calcd. for C6H16NO6P2 260.0453;
found 260.0439.
3-[(N-Benzylcarbamoyl)hydroxyphosphinoyl]propylphosphonic Acid
(4b)
thylaminobenzyl)phosphinoyl]propylphosphonate
(600 mg,
1.1 mmol), water (2.5 mL), and hydrobromic acid (47% solution,
2.58 mL). The reaction mixture was heated at reflux for 3 h. After
concentration under vacuum, the crude residue was dissolved in a
minimum of water. Acetone was added to precipitate 3d. After re-
moval of the supernatant, the residue was washed with acetone to
yield 3d (189 mg, 46%) as a yellow foam. 31P NMR (161.97 MHz,
Diethyl 3-[(N-Benzylcarbamoyl)ethoxyphosphinoyl]propylphosphon-
ate: From benzyl isocyanate (2.5 equiv.) and DMAP (0.2 equiv.)
and heating at reflux for 4 d to yield the product (1.07 g, 48%) as
4
a yellow oil. 31P NMR (161.97 MHz, CDCl3): δ = 30.18 (d, JP,P
4
1
= 5.9 Hz), 33.88 (d, JP,P = 5.9 Hz) ppm. H NMR (400.13 MHz,
3
3
1
CDCl3): δ = 1.25 (t, JH,H = 7.1 Hz, 6 H), 1.25 (t, JH,H = 7.1 Hz,
D2O): δ = 29.31 (s), 34.44 (s) ppm. H NMR (400.13 MHz, D2O):
2
2
3 H), 1.75–2.03 (m, 6 H), 3.88–4.08 (m, 6 H), 4.42 (dd, JH,H
=
δ = 1.40–1.65 (m, 6 H), 4.30 (d, JP,H = 10.4 Hz, 1 H), 7.27–7.49
3
2
2
(m, 5 H) ppm. 13C NMR (100.61 MHz, D2O): δ = 15.3 (t, JC,P
=
–14.60 Hz, JH,H = 5.27 Hz, 1 H), 4.48 (dd, JH,H = –14.60 Hz,
3JH,H = 6.08 Hz, 1 H), 7.20–7.30 (m, 5 H), 7.55 (br. m, 1 H) ppm.
13C NMR (100.61 MHz, CDCl3): δ = 14.9 (dd, 2JC,P = 4.4 Hz, 2JC,P
1
3
3.7 Hz), 27. 6 (dd, JC,P = 133.2 Hz, JC,P = 15.4 Hz), 28.3 (dd,
1JC,P = 95.9 Hz, JC,P = 16.1 Hz), 85.6 (d, JC,P = 85.6 Hz), 127.6
3
1
3
3
= 2.2 Hz), 16.3 (d, JC,P = 5.8 Hz), 16.5 (d, JC,P = 5.8 Hz), 26.1
(d, JC,P = 4.4 Hz), 128.6 (d, JC,P = 1.5 Hz), 129.1 (d, JC,P = 1.5 Hz),
1
3
1
(dd, JC,P = 95.9 Hz, JC,P = 16.1 Hz), 26.4 (dd, JC,P = 141.2 Hz,
131.1 (d, JC,P
= 2.9 Hz) ppm. HRMS (ESI): calcd. for
3JC,P = 14.6 Hz), 43.4 (d, JC,P = 5.1 Hz), 61.7 (d, JC,P = 6.6 Hz),
3
2
C10H18NO5P2 294.0660; found 294.0634.
2
62.5 (d, JC,P = 6.6 Hz), 128.0 (s), 128.90 (s), 136.7 (s), 167.8 (d,
1JC,P = 145.2 Hz) ppm. HRMS (ESI): calcd. for C17H30NO6P2
General Procedures for the Syntheses of Carbamoylphosphinates 4a–
d: Into a 50-mL two-necked flask equipped with a condenser were
introduced, respectively, 7b (1.5 g, 5.51 mmol), dry dichloroethane
(30 mL), the isocyanate (from 2 to 3 equiv.), and 4-(dimethyl-
amino)pyridine (from 0.2 to 0.5 equiv.) under nitrogen. The reac-
tion mixture was refluxed from 4 to 7 d. After concentration under
vacuum, the residue was purified by column chromatography on
silica gel (AcOEt/EtOH, from 100:0 to 50:50) to give the protected
product. Into a 50-mL two-necked flask were introduced the
carbamoyl-protected phosphinate (1 mmol) and dry dichlorometh-
ane (20 mL). The mixture was cooled in an ice bath, and trimethyl-
silyl bromide (12 mmol) was added. The reaction mixture was
stirred at room temperature overnight and then concentrated in
vacuo to dryness. Finally, methanol (20 mL) was poured into the
flask, and the resulting mixture was stirred at room temperature for
1 h and then concentrated under vacuum. After extraction using
chloroform and water, the aqueous phase was evaporated under
vacuum, and 4a–d were obtained in quantitative yield without fur-
ther purification.
406.1548; found 406.1548.
3-[(N-Benzylcarbamoyl)hydroxyphosphinoyl]propylphosphonic Acid
(4b): Yellow foam (321 mg, quantitative. 31P NMR (161.97 MHz,
4
4
D2O): δ = 27.13 (d, JP,P = 5.9 Hz), 30.27 (d, JP,P = 5.9 Hz) ppm.
1H NMR (400.13 MHz, D2O): δ = 1.59–1.79 (m, 6 H), 4.31 (s, 2
H), 7.17–7.24 (m, 5 H) ppm. 13C NMR (100.61 MHz, D2O): δ =
15.2 (dd, 2JC,P = 2.2 Hz, 2JC,P = 2.9 Hz), 27.0 (dd, 1JC,P = 133.9 Hz,
1
3
3JC,P = 15.4 Hz), 27.7 (dd, JC,P = 94.4 Hz, JC,P = 16.8 Hz), 127.2
1
(s), 127.48 (s), 128.8 (s), 137.2 (s), 173.5 (d, JC,P = 144.9 Hz) ppm.
HRMS (ESI): calcd. for C11H18NO6P2 322.0608; found 322.0609.
3-[Hydroxy(N-phenylcarbamoyl)phosphinoyl]propylphosphonic Acid
(4c)
Diethyl 3-[Ethoxy(N-phenylcarbamoyl)phosphinoyl]propylphosphon-
ate: From phenyl isocyanate (2 equiv.) and DMAP (0.3 equiv.) and
heating at reflux for 7 d to yield the product (604 mg, 28%) as a
4
yellow oil. 31P NMR (101.25 MHz, CDCl3): δ = 30.13 (d, JP,P
4
1
= 5.0 Hz), 33.93 (d, JP,P = 5.0 Hz) ppm. H NMR (400.13 MHz,
3
3
CDCl3): δ = 1.23 (t, JH,H = 7.1 Hz, 6 H), 1.28 (t, JH,H = 7.1 Hz,
3 H), 1.79–2.10 (m, 6 H), 3.96–4.06 (m, 4 H), 4.07–4.17 (m, 2 H),
7.10–7.14 (m, 1 H), 7.28–7.32 (m, 2 H), 7.61–7.63 (m, 2 H), 9.29
3-[(N-Ethylcarbamoyl)hydroxyphosphinoyl]propylphosphonic Acid
(4a)
(s, 1 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 15.0 (dd, JC,P
2
Diethyl 3-[(N-Ethylcarbamoyl)ethoxyphosphinoyl]propylphosphon-
ate: From ethyl isocyanate (3 equiv.) and DMAP (0.5 equiv.) and
heating at reflux for 5 d to yield the product (757 mg, 40%) as a
2
3
3
= 4.4 Hz, JC,P = 2.9 Hz), 16.3 (d, JC,P = 5.8 Hz), 16.4 (d, JC,P
=
5.9 Hz), 26.0 (dd, 1JC,P = 96.6 Hz, JC,P = 16.1 Hz), 26.3 (dd, JC,P
3
1
4
yellow oil. 31P NMR (101.25 MHz, CDCl3): δ = 30.03 (d, JP,P
= 141.2 Hz, 3JC,P = 14.6 Hz), 61.7 (d, 2JC,P = 6.6 Hz), 62.8 (d, 2JC,P
4
1
= 7.3 Hz), 120.0 (s), 125.65 (s), 129.16 (s), 136.6 (d, 3JC,P = 9.5 Hz),
= 6.1 Hz), 33.76 (d, JP,P = 6.1 Hz) ppm. H NMR (400.13 MHz,
3
3
1
CDCl3): δ = 1.22 (t, JH,H = 7.2 Hz, 3 H), 1.25 (t, JH,H = 7.0 Hz,
166.7 (d, JC,P
= 146.4 Hz) ppm. HRMS (ESI): calcd. for
3
6 H), 1.27 (t, JH,H = 7.0 Hz, 3 H), 1.85–2.09 (m, 6 H), 3.39–3.43
C16H28NO6P2 392.1392; found 392.1392.
(m, 2 H), 3.99–4.16 (m, 6 H), 7.20 (br. m, 1 H) ppm. 13C NMR
(100.61 MHz,CDCl3): δ = 14.2 (s), 14.7 (s), 16.1 (d, 3JC,P = 5.8 Hz),
16.2 (d, 3JC,P = 5.8 Hz), 25.8 (dd, 1JC,P = 95.9 Hz, 3JC,P = 16.1 Hz),
3-[Hydroxy(N-phenylcarbamoyl)phosphinoyl]propylphosphonic Acid
(4c): Brown foam (307 mg, quantitative). 31P NMR (161.97 MHz,
D2O): δ = 26.33 (s), 30.10 (d, 4JP,P = 5.9 Hz) ppm 1H (400.13 MHz,
D2O): δ = 1.78–1.85 (m, 6 H), 7.43–7.21 (m, 5 H) ppm. 13C NMR
1
3
3
26.1 (dd, JC,P = 141.2 Hz, JC,P = 14.6 Hz), 34.1 (d, JC,P
5.1 Hz), 61.4 (d, JC,P = 6.6 Hz), 62.1 (d, JC,P = 6.6 Hz), 167.3
(d, JC,P = 145.6 Hz) ppm. HRMS (ESI): calcd. for C12H28NO6P2
=
2
2
2
2
1
(100.61 MHz, D2O): δ = 14.0 (t, JC,P = 3.8 Hz, JC,P = 2.9 Hz),
3
26.3–28.9 (m), 122.52 (s), 126.4 (s), 129.2 (s), 135.5 (dd, JC,P
=
344.1388; found 344.1392.
8.8 Hz), 174.9 (s) ppm. HRMS (ESI): calcd. for C10H16NO6P2
308.0450; found 308.0453.
3-[(N-Ethylcarbamoyl)hydroxyphosphinoyl]propylphosphonic Acid
(4a): Yellow oil (259 mg, quantitative). 31P NMR (161.97 MHz,
3-[(N-4-Fluorophenylcarbamoyl)hydroxyphosphinoyl]propylphos-
phonic Acid (4d)
4
4
D2O): δ = 27.62 (d, JP,P = 6.5 Hz), 30.24 (d, JP,P = 6.5 Hz) ppm.
1H NMR (400.13 MHz, D2O): δ = 0.99 (t, JH,H = 7.2 Hz, 3 H),
3
1.59–1.82 (m, 6 H), 3.15 (q, JH,H = 7.2 Hz, 2 H) ppm. 13C NMR
Diethyl 3-[Ethoxy(N-4-fluorophenylcarbamoyl)phosphinoyl]propyl-
phosphonate: From 4-fluorophenyl isocyanate (2 equiv.) and
DMAP (0.3 equiv.) and heating at reflux for 4 d to yield the prod-
uct (564 mg, 25 %) as a brown foam. 31P NMR (101.25 MHz,
3
2
2
(100.61 MHz, D2O): δ = 13.4 (s), 15.1 (dd, JC,P = 2.2 Hz, JC,P
=
2.9 Hz), 27.0 (dd, 1JC,P = 133.9 Hz, 3JC,P = 15.4 Hz), 27.5 (dd, 1JC,P
= 93.7 Hz, 3JC,P = 16.1 Hz), 34.2 (d, 3JC,P = 5.1 Hz), 172.8 (d, 1JC,P
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
Fosmidomycin Analogues
2
2
CDCl3): δ = 30.09 (d, 4JP,P = 5.9 Hz), 33.92 (d, 4JP,P = 5.9 Hz) ppm. = 15.4 Hz), 61.0 (d, JC,P = 6.6 Hz), 61.6 (d, JC,P = 5.9 Hz), 123.1
3
1
3
3
1H NMR (400.13 MHz, CDCl3): δ = 1.24 (t, JH,H = 7.2 Hz, 6 H),
(d, JC,P = 123.1 Hz), 123.7 (d, JC,P = 6.6 Hz), 126.3 (d, JC,P =
11.0 Hz), 134.0 (d, JC,P = 1.5 Hz), 135.1 (d, JC,P = 5.8 Hz), 152.1
(d, JC,P = 3.7 Hz), 169.1 (s) ppm. HRMS (ESI): calcd. for
C17H29O7P2 407.1389; found 407.1380.
3
4
2
1.30 (t, JH,H = 7.0 Hz, 3 H), 1.77–2.11 (m, 6 H), 3.95–4.14 (m, 6
H), 6.97–7.02 (m, 2 H), 7.54–7.55 (m, 2 H), 8.92 (s, 1 H) ppm. 13C
2
2
2
NMR (100.61 MHz, CDCl3): δ = 15.0 (dd, JC,P = 3.7 Hz, JC,P
=
2.9 Hz), 16.2 (d, 3JC,P = 5.8 Hz), 16.3 (d, JC,P = 5.8 Hz), 26.0 (dd,
3
Diethyl 3-[Ethoxy(2-methoxyphenyl)phosphinoyl]propylphosphonate
(12c): Colorless oil (849 mg, 61 %). 31P NMR (161.97 MHz,
CDCl3): δ = 30.95 (d, 4JP,P = 5.9 Hz), 42.04 (d, 4JP,P = 5.9 Hz) ppm.
1JC,P = 96.7 Hz, JC,P = 15.4 Hz), 26.2 (dd, JC,P = 142.0 Hz, JC,P
3
1
3
2
2
= 15.4 Hz), 61.6 (d, JC,P = 6.6 Hz), 62.7 (d, JC,P = 7.3 Hz), 115.5
(d, JC,F = 22.7 Hz), 122.1 (d, JC,F = 8.0 Hz), 133.1 (d, JC,P
10.2 Hz), 159.8 (d, JC , F = 245.2 Hz), 166.2 (d, JC , P
2
3
3
=
=
1H NMR (400.13 MHz, CDCl3): δ = 1.24 (t, JH,H = 7.0 Hz, 3 H),
3
1
1
3
3
1.27 (t, JH,H = 7.0 Hz, 3 H), 1.29 (t, JH,H = 7.7 Hz, 3 H), 1.75–
2.24 (m, 6 H), 3.72–3.84 (m, 1 H), 3.88 (s, 3 H), 3.99–4.11 (m, 5
H), 6.94 (dd, 3JH,H = 8.3 Hz, 4JH,P = 5.7 Hz, 1 H), 7.07 (tdd, 3JH,H
= 7.5 Hz, JH,P = 1.8 Hz, JH,H = 0.9 Hz, 1 H), 7.53 (dddd, JH,H
= 8.3 Hz, JH,H = 7.5 Hz, JH,P = 2.2 Hz, JH,H = 1.8 Hz, 1 H),
147.1 Hz) ppm. HRMS (ESI): calcd. for C16H27FNO6P2 410.1294;
found 410.1298.
4
4
3
3-[(N-4-Fluorophenylcarbamoyl)hydroxyphosphinoyl]propylphos-
phonic Acid (4d): Yellow foam (325 mg, quantitative). 31P NMR
3
5
4
4
3
3
4
(161.97 MHz, D2O): δ = 26.64 (s), 30.35 (d, JP,P = 5.9 Hz) ppm.
7.92 (ddd, JH,P = 12.8 Hz, JH,H = 7.5 Hz, JH,H = 1.8 Hz, 1
1H NMR (400.13 MHz, D2O): δ = 1.67–1.83 (m, 6 H), 7.00–7.04
H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 15.3 (t, JC,P
=
2
(m, 2 H), 7.31–7.34 (m, 2 H) ppm. 13C NMR (100.61 MHz, D2O):
2.9 Hz), 16.3–16.4 (m), 26.4 (dd, 1JC,P = 140.5 Hz, 3JC,P = 14.6 Hz),
2
2
1
3
2
δ = 14.0 (t, JC,P = 3.7 Hz, JC,P = 2.9 Hz), 26.9 (dd, JC,P
=
=
29.7 (dd, 1JC,P = 102.5 Hz, JC,P = 16.1 Hz), 55.5 (s), 60.4 (d, JC,P
3
1
3
2
3
133.9 Hz, JC,P = 15.4 Hz), 27.4 (dd, JC,P = 94.4 Hz, JC,P
= 6.6 Hz), 61.5 (d, JC,P = 6.6 Hz), 110.8 (d, JC,P = 7.3 Hz), 117.8
(d, JC,P = 120.7 Hz), 120.8 (d, JC,P = 11.7 Hz), 134.5 (d, JC,P =
2.2 Hz), 135.7 (d, JC,P = 5.8 Hz), 160.6 (d, JC,P = 4.4 Hz) ppm.
HRMS (ESI): calcd. for C16H29O6P2 379.1439; found 379.1417.
16.8 Hz), 115.6 (d, 2JC,F = 23.4 Hz), 124.3 (d, 3JC,F = 8.8 Hz), 131.3
1
3
4
3
3
1
2
1
(dd, JC,P = 8.8 Hz, JC,F = 2.2 Hz), 160.2 (d, JC,F = 243.0 Hz),
171.6 (d, JC,P = 147.8 Hz) ppm. HRMS (ESI): calcd. for
1
C10H15FNO6P2 326.0347; found 326.0359.
Diethyl 3-[(2-Acetylaminophenyl)ethoxyphosphinoyl]propylphos-
General Procedure for the Coupling Between 7b and Substituted
Bromobenzene Using Palladium Dichloride: Into a 25-mL two-
necked flask equipped with a condenser were introduced palladium
dichloride (64 mg, 0.368 mmol), triphenylphosphane (292 mg,
1.104 mmol), and dry toluene (10 mL). The mixture was stirred
at room temperature for 5 min. Then, 7b (1.0 g, 3.68 mmol), the
phonate (12d): Light yellow oil (760 mg, 51 %). 31P NMR
4
4
(161.97 MHz, CDCl3): δ = 30.32 (d, JP,P = 4.0 Hz), 49.32 (d, JP,P
1
3
= 4.0 Hz) ppm. H NMR (400.13 MHz, CDCl3): δ = 1.20 (t, JH,H
= 7.0 Hz, 3 H), 1.23 (t, JH,H = 7.0 Hz, 3 H), 1.25 (t, JH,H
3
3
=
7.1 Hz, 3 H), 1.73–2.02 (m, 6 H), 2.13 (s, 3 H), 3.78–3.84 (m, 1 H),
3.95–4.09 (m, 5 H), 7.04 (tdd, 3JH,H = 7.4 Hz, 4JH,P = 2.8 Hz, 4JH,H
3
3
4
substituted bromobenzene derivatives (5.52 mmol), and triethyl- = 0.9 Hz, 1 H), 7.22 (ddd, JH,P = 13.1 Hz, JH,H = 7.4 Hz, JH,H
3
4
amine (1.54 mL, 11.04 mmol) were added. The reaction mixture
was stirred at reflux for 14 h and then concentrated under vacuum.
The crude residue was dissolved in ethyl acetate (50 mL), and the
resulting mixture was filtered through Celite. The filtrate was con-
centrated, and the residue was purified by column chromatography
on silica gel (EtOAc/EtOH, from 100:0 to 85:15).
= 1.4 Hz, 1 H), 7.53 (ddd, 3JH,H = 8.5 Hz, JH,H = 7.4 Hz, JH,H
=
=
3
4
4
1.4 Hz, 1 H), 8.55 (ddd, JH,H = 8.5 Hz, JH,P = 5.1 Hz, JH,H
0.9 Hz, 1 H), 11.05 (s, 1 H) ppm. 13C NMR (100.61 MHz, CDCl3):
2
2
δ = 15.2 (dd, JC,P = 4.4 Hz, JC,P = 2.9 Hz), 16.3–16.5 (m): δ =
1
3
25.28 (s), 26.2 (dd, JC,P = 141.2 Hz, JC,P = 15.4 Hz), 30.8 (dd,
1JC,P = 103.2 Hz, JC,P = 13.9 Hz), 61.3 (d, JC,P = 7.3 Hz), 61.6
3
2
2
1
3
(d, JC,P = 5.9 Hz), 114.6 (d, JC,P = 116.4 Hz), 120.7 (d, JC,P
=
Diethyl 3-(Ethoxy-phenylphosphinoyl)propylphosphonate (12a): Col-
orless oil (794 mg, 62%). 31P NMR (161.97 MHz, CDCl3): δ =
3
2
8.0 Hz), 122.9 (d, JC,P = 12.4 Hz), 131.5 (d, JC,P = 8.8 Hz), 134.0
(d, 4JC,P = 2.2 Hz), 143.0 (d, 1JC,P = 5.1 Hz), 169.1 (s) ppm. HRMS
(ESI): calcd. for C17H30NO6P2 406.1548; found 406.1527.
4
4
1
30.63 (d, JP,P = 5.3 Hz), 43.53 (d, JP,P = 5.3 Hz) ppm. H NMR
3
(400.13 MHz, CDCl3): δ = 1.19 (t, JH,H = 7.0 Hz, 3 H), 1.21 (t,
3JH,H = 7.0 Hz, 3 H), 1.23 (t, JH,H = 7.2 Hz, 3 H) 1.70–2.04 (m, 6 General Procedure for the Coupling of 7b and Substituted Heteroaryl
3
H), 3.72–3.85 (m, 1 H), 3.92–4.06 (m, 5 H), 7.39–7.45 (m, 2 H),
7.47–7.52 (m, 1 H), 7.67–7.74 (m, 2 H) ppm. 1 3 C NMR
(100.61 MHz, CDCl3): δ = 15.5 (dd, 2JC,P = 4.4 Hz, 2JC,P = 2.9 Hz),
Halides Using Bis(dibenzylidene)dipalladium: Into a 25-mL two-
necked flask equipped with a condenser were introduced bis(tri-
benzylidene)dipalladium (169 mg, 0.184 mmol), (diphenylphos-
phanyl)ferrocene (204 mg, 0.368 mmol), and dry toluene (15 mL).
The mixture was stirred at room temperature for 5 min. Finally, 7b
(1 g, 3.68 mmol), the heteroaryl halide (5.52 mmol), and triethyl-
amine (1. 54 mL, 11.04 mmol) were successively added, and the
reaction mixture was stirred at 80 °C for 12 h. The mixture was
concentrated under vacuum, and the resulting residue was dis-
solved in ethyl acetate (50 mL). The mixture was filtered through
Celite. The filtrate was concentrated, and the residue was purified
using different techniques depending on the substrate.
1
3
16.4–16.5 (m), 26.3 (dd, JC,P = 140.5 Hz, JC,P = 15.1 Hz), 30.3
1
3
2
(dd, JC,P = 100.3 Hz, JC,P = 14.6 Hz), 60.6 (d, JC,P = 6.6 Hz),
61.6 (d, 2JC,P = 6.6 Hz), 128.7 (d, 3JC,P = 12.4 Hz), 130.5 (d, 1JC,P
=
123.7 Hz), 131.6 (d, 2JC,P = 10.2 Hz), 132.4 (d, 4JC,P = 2.9 Hz) ppm.
HRMS (ESI): calcd. for C15H27O5P2 349.1334; found 349.1319.
Diethyl 3-[(2-Acetyloxyphenyl)ethoxyphosphinoyl]propylphosphon-
ate (12b): Colorless oil (807 mg, 54%). 31P NMR (161.97 MHz,
CDCl3): δ = 30.64 (d, 4JP,P = 5.9 Hz), 40.33 (d, 4JP,P = 5.9 Hz) ppm.
3
1H NMR (400.13 MHz, CDCl3): δ = 1.18 (t, JH,H = 7.0 Hz, 3 H),
3
3
1.21 (t, JH,H = 7.0 Hz, 3 H), 1.23 (t, JH,H = 7.1 Hz, 3 H), 1.72–
Diethyl 3-[Ethoxy(2-pyridyl)phosphinoyl]propylphosphonate (13a): 2-
2.20 (m, 6 H), 2.26 (s, 3 H), 3.60–3.69 (m, 1 H), 3.92–4.09 (m, 5
H), 7.07 (ddd, JH,H = 8.1 Hz, JH,P = 4.8 Hz, JH,H = 0.9 Hz, 1 The crude material was purified by column chromatography on
Bromopyridine was used as the starting material for this reaction.
3
4
4
3
4
4
H), 7.31 (tdd, JH,H = 7.6 Hz, JH,P = 2.3 Hz, JH,H = 0.9 Hz, 1
silica gel (EtOAc/EtOH, from 100:0 to 80:20) to yield the product
(950 mg, 74%) as a yellow oil. 31P NMR (161.97 MHz, CDCl3): δ
= 30.59 (d, 4JP,P = 6.9 Hz), 40.14 (d, 4JP,P = 6.9 Hz) ppm. 1H NMR
3
3
4
H), 7.53 (dddd, JH,H = 8.1 Hz, JH,H = 7.6 Hz, JH,H
=
5JH,P
=
=
3
3
4
1.8 Hz, 1 H), 7.89 (ddd, JH,H = 7.6 Hz, JH,P = 12.4 Hz, JH,H
1.8 Hz, 1 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ = 15.3 (dd,
(400.13 MHz, CDCl3): δ = 1.27 (t, JH,H = 7.0 Hz, 3 H), 1.28 (t,
3
2
3
2JC,P = 2.9 Hz, JC,P = 4.4 Hz), 16.2–16.5 (m), 21.15 (s), 26.3 (dd,
3JH,H = 7.1 Hz, 3 H), 1.30 (t, JH,H = 7.0 Hz, 3 H), 1.81–2.22 (m,
1JC,P = 141.1 Hz, 3JC,P = 14.6 Hz), 30.2 (dd, 1JC,P = 103.2 Hz, 3JC,P
6 H), 3.80–3.89 (m, 1 H), 4.02–4.14 (m, 5 H), 7.44 (dddd, JH,H
=
3
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
D. Virieux et al.
3 H), 1.24 (t, JH,H = 7.1 Hz, 3 H), 1.75–2.03 (m, 6 H), 3.84–3.91
FULL PAPER
3
5
4
3
7.8 Hz, JH,H = 4.8 Hz, JH,P = 2.1 Hz, JH,H = 1.2 Hz, 1 H), 7.84
4
3
3
4
3
3
(dddd, JH,P = 10.0 Hz, JH,H = 7.8 Hz, JH,H = 7.7 Hz, JH,H
=
=
=
(m, 1 H), 3.95–4.09 (m, 5 H), 7.15 (ddd, JH,H = 4.8 Hz, JH,H
=
3
3
4
4
3 or 4
3
1.6 Hz, 1 H), 8.07 (dddd, JH,H = 7.7 Hz, JH,P = 5.5 Hz, JH,H
3.6 Hz, JH,P = 2.3 Hz, 1 H), 7.55 (ddd,
= 3.6 Hz, JH,H = 1.0 Hz, 1 H), 7.67 (ddd, JH,H = 4.8 Hz,
J
= 6.8 Hz, JH,H
H,P
3
5
3
4
4
1.2 Hz, JH,H = 1.1 Hz, 1 H), 8.79 (ddd, JH,H = 4.8 Hz, JH,H
5
3 or 4
3
1.6 Hz, JH,H = 1.1 Hz, 1 H) ppm. 13C NMR (100.61 MHz,
J
= 4.6 Hz, JH ,H = 1.0 Hz, 1 H) ppm. 13 C NMR
H,P
2
3
2
CDCl3): δ = 15.4 (t, JC,P = 3.7 Hz), 16.4 (d, JC,P = 5.8 Hz), 26.4
(100.61 MHz, CDCl3): δ = 15.1 (t, JC,P = 3.7 Hz), 16.3–16.4 (m),
26.1 (dd, JC,P = 141.2 Hz, JC,P = 15.4 Hz), 31.4 (dd, JC,P
108.3 Hz, JC,P = 15.4 Hz), 61.0 (d, JC,P = 6.6 Hz), 61.5 (d, JC,P
= 6.6 Hz), 128.4 (d, JC,P = 14.6 Hz), 130.8 (d, JC,P = 133.8 Hz),
1
3
1
(dd, 1JC,P = 140.5 Hz, 3JC,P = 14.6 Hz), 27.9 (dd, 1JC,P = 101.0 Hz,
=
2
2
3
2
2
3JC,P = 16.4 Hz), 61.1 (d, JC,P = 6.6 Hz), 61.5 (d, JC,P = 6.6 Hz),
3
1
126.0 (d, 4JC,P = 3.7 Hz), 128.3 (d, 2JC,P = 21.2 Hz), 136.2 (d, 3JC,P
3
1
3
2
= 9.5 Hz), 150.5 (d, JC , P = 19.7 Hz), 153.8 (d, JC , P
=
133.6 (d, JC,P = 5.5 Hz), 136.4 (d, JC,P = 10.9 Hz) ppm. HRMS
153.0 Hz) ppm. HRMS (ESI): calcd. for C14H26NO5P2 350.1286;
found 350.1285.
(ESI): calcd. for C13H25O5P2S 355.0898; found 355.0890.
Diethyl 3-[Ethoxy(2-pyrimidinyl)phosphinoyl]propylphosphonate
(13e): 2-Chloropyrimidine was used as the starting material. The
crude material was purified by column chromatography on silica
gel (EtOAc/EtOH, from 100:0 to 85:15) to yield the product
(876 mg, 68%) as a yellow oil. 31P NMR (161.97 MHz, CDCl3): δ
= 30.52 (d, 4JP,P = 6.9 Hz), 35.95 (d, 4JP,P = 6.9 Hz) ppm. 1H NMR
(400.13 MHz, CDCl3): δ = 1.26–1.34 (m, 9 H), 1.83–2.29 (m, 6 H),
4.01–4.11 (m, 4 H), 4.14–4.24 (m, 1 H), 4.26–4.40 (m, 1 H), 7.41
(m, 1 H), 7.84 (m, 2 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ
Diethyl 3-[Ethoxy-(1-methylimidazol-5-yl)phosphinoyl]propylphos-
phonate (13b): 5-Bromo-1-methyl-1H-imidazole was used as the
starting material. The target compound was not stable on silica gel
and was purified by extraction. The first extraction of the crude
material was performed using hexane and acetonitrile. The acetoni-
trile layer was concentrated, and the residue was dissolved in chlo-
roform. The resulting mixture was washed with water. The chloro-
form phase was dried with MgSO4 and concentrated. The residue
was dissolved in a minimum amount of chloroform, and ether was
added. The filtrate was concentrated, and the oil obtained was trit-
urated with ether (4ϫ). The combined filtrates were concentrated,
and the oil obtained triturated with hexane (4ϫ). Finally, the oily
residue was dissolved in ether, and the mixture was treated with
active charcoal. The filtrate was extracted with water, and the aque-
ous phase was concentrated to dryness to yield the product
(380 mg, 30%) as a colorless oil. 31P NMR (161.97 MHz, CDCl3):
2
3
3
= 15.2 (t, JC,P = 4.4 Hz), 16.3 (d, JC,P = 6.6 Hz), 16.4 (d, JC,P
=
5.9 Hz), 26.4 (dd, 1JC,P = 140.5 Hz, 3JC,P = 14.6 Hz), 27.6 (dd, 1JC,P
= 101.0, JC,P = 16.1 Hz), 61.5 (d, JC,P = 6.6 Hz), 62.1 (d, JC,P
7.3 Hz), 122.3 (d, JC,P = 2.9 Hz), 156.9 (d, JC,P = 14.6 Hz), 166.0
(d, 1JC,P = 185.9 Hz) ppm. HRMS (ESI): calcd. for C13H25N2O5P2
351.1239; found 351.1246.
3
2
2
=
4
3
Diethyl 3-{Ethoxy[5-(trifluoromethyl)pyridin-2-yl]phosphinoyl}-
propylphosphonate (13f): 2-Chloro-4-(trifluoromethyl)pyridine was
used as the starting material. The crude material was purified by
column chromatography on silica gel (EtOAc/EtOH, from 100:0 to
70:30) to yield the product (1.00 g, 66%) as a colorless oil. 31P
4
4
δ = 30.43 (d, JP,P = 4.9 Hz), 33.62 (d, JP,P = 4.9 Hz) ppm. 1H
NMR (400.13 MHz, CDCl3): δ = 1.21–1.29 (m, 9 H), 1.75–1.99 (m,
6 H), 3.83 (s, 3 H), 3.88–3.94 (m, 1 H), 3.94–4.04 (m, 4 H), 4.04–
4
4.12 (m, 1 H), 7.37 (s, 1 H), 7.53 (d, 3JH,P = 2.1 Hz, 1 H) ppm. 13
C
=
NMR (161.97 MHz, CDCl3): δ = 30.36 (d, JP,P = 5.9 Hz), 38.89
4
(d, JP,P = 5.9 Hz) ppm. 19F NMR (376.50 MHz, CDCl3): δ =
2
2
NMR (100.61 MHz, CDCl3): δ = 15.3 (dd, JC,P = 4.4 Hz, JC,P
1
2.9 Hz), 16.3 (d, 3JC,P = 6.6 Hz), 16.4 (d, JC,P = 5.9 Hz), 26.0 (dd,
3
–62.80 (s, 3 F) ppm. H NMR (400.13 MHz, CDCl3): δ = 1.21 (t,
3
3
3JH,H = 7.0 Hz, 3 H), 1.22 (t, JH,H = 7.1 Hz, 3 H), 1.24 (t, JH,H
1JC,P = 141.24 Hz, JC,P = 15.4 Hz), 31.3 (dd, JC,P = 109.0 Hz,
3
1
3JC,P = 13.9 Hz), 33.7 (s), 61.2 (d, JC,P = 6.6 Hz), 61.6 (d, JC,P
=
2
2
= 7.0 Hz, 3 H), 1.75–2.20 (m, 6 H), 3.78–3.85 (m, 1 H), 3.95–4.10
3
3
4
1
2 or 3
(m, 5 H), 8.03 (dddd, JH,H = 7.9 Hz, JH,P = 3.1 Hz, JH,H
=
=
6.6 Hz), 121.8 (d, JC,P = 147.1 Hz), 139.7 (d,
J
C,P
= 16.1 Hz),
4
3
3
2 or 3
2.0 Hz, JH,F = 0.7 Hz, 1 H), 8.15 (dd, JH,H = 7.9 Hz, JH,P
143.0 (d,
J
= 11.7 Hz) ppm. HRMS (ESI): calcd. for
C,P
5.1 Hz, 1 H), 8.96 (s, 1 H) ppm. 13C NMR (100.61 MHz, CDCl3):
C13H27N2O5P2 353.1395; found 353.1390.
2
2
3
δ = 15.2 (dd, JC,P = 4.4 Hz, JC,P = 2.9 Hz), 16.3 (d, JC,P
=
Diethyl 3-[Ethoxy(2-thiazolyl)phosphinoyl]propylphosphonate (13c):
2-Bromothiazole was used as the starting material for this reaction.
The crude material was purified by column chromatography on
silica gel (EtOAc/EtOH, from 100:0 to 85:15) to yield the product
(845 mg, 65%) as a yellow oil. 31P NMR (161.97 MHz, CDCl3): δ
= 30.35 (d, 4JP,P = 5.9 Hz), 34.30 (d, 4JP,P = 5.9 Hz) ppm. 1H NMR
(400.13 MHz, CDCl3): δ = 1.27–1.32 (m, 9 H), 1.82–2.27 (m, 6 H),
3.84–3.99 (m, 1 H), 4.01–4.18 (m, 4 H), 4.14–4.23 (m, 1 H), 7.73
(dd, 3JH,H = 2.9 Hz, 4JH,P = 2.9 Hz, 1 H), 8.15 (dd, 3JH,H = 2.9 Hz,
4JH,P = 1.1 Hz, 1 H) ppm. 13C NMR (100.61 MHz, CDCl3): δ =
5.8 Hz), 26.3 (dd, 1JC,P = 141.2 Hz, 3JC,P = 14.6 Hz), 27.7 (dd, 1JC,P
= 101.0 Hz, 3JC,P = 15.4 Hz), 61.4 (d, 2JC,P = 6.6 Hz), 61.5 (d, 2JC,P
1
3
= 6.6 Hz), 122.9 (q, JC,F = 274.4 Hz), 127.9 (d, JC,P = 21.2 Hz),
2
4
3
128.46 (qd, JC,F = 32.9 Hz, JC,P = 2.9 Hz), 131.9 (dq, JC,P
=
9.5 Hz, 3JC,F = 2.9 Hz), 147.1 (dq, 3JC,P = 20.5 Hz, 3JC,F = 3.7 Hz),
1
158.0 (d, JC,P = 149.3 Hz) ppm. HRMS (ESI): calcd. for
C15H25F3NO5P2 418.1160; found 418.1167.
3-(Hydroxy-phenylphosphinoyl)propylphosphonic Acid (5a): Into a
25-mL two-necked flask equipped with a condenser were intro-
duced, respectively, 12a (300 mg, 0.861 mmol), water (1.6 mL), and
hydrochloric acid (35% solution, 1.6 mL). The reaction mixture
was heated to reflux for 20 h and then concentrated under vacuum
to yield the product (200 mg, 88%) as a white foam. 31P NMR
2
3
3
15.2 (t, JC,P = 4.4 Hz), 16.3 (d, JC,P = 6.6 Hz), 16.4 (d, JC,P
=
1
3
5.9 Hz), 26.2 (dd, JC,P = 141.25 Hz, JC,P = 15.4 Hz), 29.3 (dd,
1JC,P = 106.8 Hz, JC,P = 16.1 Hz), 61.6 (d, JC,P = 6.6 Hz), 61.9
3
2
2
3
(d, JC,P = 6.6 Hz), 125.2 (s), 146.2 (d, JC,P = 22.7 Hz), 161.9 (d,
1JC,P = 155.14 Hz) ppm. HRMS (ESI): calcd. for C12H24NO5P2S
356.0850; found 356.0850.
4
4
(161.97 MHz, D2O): δ = 29.33 (d, JP,P = 5.9 Hz), 43.34 (d, JP,P
=
5.9 Hz) ppm. 1H NMR (400.13 MHz, D2O): δ = 1.56–1.72 (m, 4
H), 1.89–1.97 (m, 2 H), 7.40–7.46 (m, 2 H), 7.49–7.54 (m, 1 H),
7.60–7.66 (m, 2 H) ppm. 13C NMR (100.61 MHz, D2O): δ = 15.59
Diethyl 3-[Ethoxy(2-thienyl)phosphinoyl]propylphosphonate (13d): 2-
Bromothiophene was used as the starting material. The crude mate-
rial was purified by column chromatography on silica gel (EtOAc/
2
1
3
(t, JC,P = 3.9 Hz, CH2-2), 27.18 (dd, JC,P = 134.7 Hz, JC,P
=
1
3
16.1 Hz, CH2-1), 29.96 (dd, JC,P = 96.6, JC,P = 16.1 Hz, CH2-3),
EtOH, from 100:0 to 80:20) to yield the product (640 mg, 50%) as 128.81 (d, 3JC,P = 13.2 Hz, CH-6), 130.68 (d, JC,P = 10.2 Hz, CH-
2
4
1
4
a yellow oil. 31P NMR (161.97 MHz, CDCl3): δ = 30.52 (d, JP,P
5), 131.05 (d, JC,P = 127.3 Hz, C-4), 132.63 (d, JC,P = 2.2 Hz,
CH-7) ppm. HRMS (ESI): calcd. for C9H15O5P2 265.0395; found
265.0392.
4
1
= 5.9 Hz), 37.22 (d, JP,P = 5.9 Hz) ppm. H NMR (400.13 MHz,
3
3
CDCl3): δ = 1.22 (t, JH,H = 7.0 Hz, 3 H), 1.23 (t, JH,H = 7.0 Hz,
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
Fosmidomycin Analogues
General Procedure for the Deprotection of Substituted Arylphos- = 109.0 Hz) ppm. HRMS (ESI): calcd. for C8H14NO5P2 266.0347;
phinoylphosphonates Using Trimethylsilyl Bromide: Into a 50-mL
three-necked flask were introduced 12b or 12d (1 mmol) and dry
dichloromethane (10 mL). The solution was cooled in an ice bath,
and trimethylsilyl bromide (1.9 mL, 15 mmol) was added. The reac-
tion mixture was stirred at room temperature for 14 h and concen-
trated to dryness under vacuum. Finally, methanol (10 mL) was
added, and the resulting mixture was stirred at room temperature
for 2 h. The reaction mixture was concentrated under vacuum, and
the crude residue was dissolved once again in methanol (10 mL).
Aqueous HCl (1 m solution, 2 mL) was added, and the resulting
solution was stirred at room temperature for 16 h. After concentra-
tion under vacuum, the desired compound was obtained.
found 266.0340.
3-(Hydroxy-2-thienylphosphinoyl)propylphosphonic Acid (6d): Yel-
low oil (235 mg, 87%). 31P NMR (161.97 MHz, D2O): δ = 29.94
(s), 35.88 (s) ppm. 1H NMR (400.13 MHz, D2O): δ = 1.50–1.60 (m,
3 or 4
4 H), 1.79–1.85 (m, 2 H), 7.02 (s, 1 H), 7.55 (dd,
J
= 7.0 Hz,
H,P
3JH,H = 3.3 Hz, 1 H), 7.67 (t, JH,H = 4.7 Hz,
J
H,P
= 4.7 Hz, 1
3
3 or 4
H) ppm. 13C NMR (100.61 MHz, D2O): δ = 15.7 (t, JC,P
=
2
3.7 Hz), 27.0 (dd, 1JC,P = 133.9 Hz, 3JC,P = 15.4 Hz), 31.4 (dd, 1JC,P
3
3
= 103.9 Hz, JC,P = 16.8 Hz), 128.6 (d, JC,P = 14.6 Hz), 132.4 (d,
1JC,P = 137.6 Hz), 133.5 (d, JC,P = 5.8 Hz), 135.4 (d, JC,P
=
3
2
10.9 Hz) ppm. HRMS (ESI): calcd. for C7H13O5P2S 270.9959;
found 270.9953.
3-[Hydroxy(2-hydroxyphenyl)phosphinoyl]propylphosphonic Acid
3-Hydroxy-[2-(5-trifluoromethylpyridyl)phosphinoyl]propylphos-
phonic Acid (6f): Yellow oil (303 mg, 91%). 31P NMR
(161.97 MHz, D2O): δ = 26.47 (br. s), 30.12 (d, 4JP,P = 5.9 Hz) ppm.
(5b): Slightly yellow foam (250 mg, 89%). 31P NMR (161.97 MHz,
4
4
D2O): δ = 30.04 (d, JP,P = 5.9 Hz), 44.25 (d, JP,P = 5.9 Hz) ppm.
1H NMR (400.13 MHz, D2O): δ = 1.57–1.72 (m, 4 H), 1.98–2.08
1
19F NMR (376.50 MHz, D2O): δ = –63.21 (s, 3 F) ppm. H NMR
3
4
(m, 2 H), 6.82 (dd, JH,H = 8.0 Hz, JH,P = 5.6 Hz, 1 H), 6.9 (td,
3JH,H = 8.0 Hz, 4JH,P = 2.4 Hz, 1 H), 7.36 (td, 3JH,H = 8.0 Hz, 4JH,P
(400.13 MHz, D2O): δ = 1.53–1.77 (m, 4 H), 1.88–1.98 (m, 2 H),
3
3
8.29 (d, JH,H = 7.8 Hz, 1 H), 8.73 (d, JH,H = 7.8 Hz, 1 H), 9.14
3
3
4
= 0.9 Hz, 1 H), 7.46 (ddd, JH,P = 13.0 Hz, JH,H = 8.0 Hz, JH,H
(s, 1 H) ppm. 13C NMR (100.61 MHz, D2O): δ = 15.4 (t, JC,P
=
2
= 2.4 Hz, 1 H) ppm. 13C NMR (100.61 MHz, D2O): δ = 15.3 (t,
2.9 Hz), 26.9 (dd, 1JC,P = 134.7 Hz, 3JC,P = 16.8 Hz), 30.2 (dd, 1JC,P
2JC,P = 2.7 Hz), 26.9 (dd, JC,P = 134.6 Hz, JC,P = 16.1 Hz), 29.7
1
3
= 103.2 Hz, 3JC,P = 16.1 Hz), 121.5 (q, 1JC,F = 272.9 Hz), 129.8 (d,
1
3
1
(dd, JC,P = 97.3 Hz, JC,P = 16.1 Hz), 115.7 (d, JC,P = 125.9 Hz,
3JC,P = 12.4 Hz), 130.2 (s), 141.83 (s), 142.3 (s), 156.3 (d, JC,P
=
1
C-4), 116.1 (d, 3JC,P = 8.0 Hz), 120.1 (d, 3JC,P = 11.7 Hz), 132.5 (d,
115.9 Hz) ppm. HRMS (ESI): calcd. for C9H13NO5P2F3 334.0221;
found 334.0212.
4JC,P = 6.6 Hz), 134.9 (d, JC,P = 2.2 Hz), 158.5 (d, JC,P
=
2
1
5.1 Hz) ppm. HRMS (ESI): calcd. for C9H15O6P2 281.0344; found
281.03400.
General Procedure for the Deprotection Using Lithium Bromide:
Into a 5-mL sealed tube were introduced 13c or 13e (0.43 mmol)
and dry acetonitrile (5 mL). The solution was stirred at room tem-
perature, and lithium bromide (225 mg, 2.6 mmol) was added. The
resulting mixture was heated at reflux and stirred for 5 d. After
cooling, the white solid formed was filtered and washed with aceto-
nitrile. The solid was dried under vacuum.
2-[Hydroxy(3-phosphonopropyl)phosphinoyl]benzenammonium
Chloride (5d): Yellow oil (283 mg, 90%). 31P NMR (161.97 MHz,
4
D2O): δ = 30.19 (d, JP, P = 6.9 Hz), 39.27 (s) ppm. 1H NMR
(400.13 MHz, D2O): δ = 1.56–1.72 (m, 4 H), 1.85–1.92 (m, 2 H),
3
4
3
7.32 (dd, JH,H = 7.8 Hz, JH,P = 4.1 Hz, 1 H), 7.47 (t, JH,H
=
=
3
3
7.8 Hz, 1 H), 7.57 (t, JH,H = 7.5 Hz, 1 H), 7.66 (ddd, JH,P
3
4
12.3 Hz, JH,H = 7.5 Hz, JH,H = 1.2 Hz, 1 H) ppm. 13C NMR
Dilithium Compound 4c: Yellow solid (127 mg, 95%). 31P NMR
2
1
(100.61 MHz, D2O): δ = 15.1 (t, JC,P = 2.9 Hz), 26.7 (dd, JC,P
=
4
4
(161.97 MHz, D2O): δ = 26.17 (d, JP,P = 7.9 Hz), 27.30 (d, JP,P
=
=
134.7, 3JC,P = 16.8 Hz), 31.6 (dd, 1JC,P = 99.5 Hz, 3JC,P = 15.4 Hz),
7.9 Hz) ppm. 1H NMR (400.13 MHz, D2O): δ = 1.04 (t, JH,H
3
3
1
124.3 (d, JC,P = 8.1 Hz), 126.0 (d, JC,P = 100.7 Hz), 129.4 (d,
3JC,P = 11.0 Hz), 132.0 (d, 2JC,P = 3.6 Hz), 133.2 (d, 2JC,P = 8.0 Hz),
7.0 Hz, 3 H), 1.40–1.51 (m, 4 H), 1.82–1.90 (m, 2 H), 3.69 (qu,
3
4
3JH,H
=
3JH,P = 7.0 Hz, 2 H), 7.72 (dd, JH,H = 2.9 Hz, JH,P
=
4
133.6 (d, JC , P = 1.4 Hz) ppm. HRMS (ESI): calcd. for
1.9 Hz, 1 H), 7.94 (d, JH,H = 2.9 Hz, 1 H) ppm. 13C NMR
3
C9H16NO5P2 280.0504; found 280.0500.
3
2
(100.61 MHz, D2O): δ = 15.8 (d, JC,P = 5.8 Hz), 16.7 (t, JC,P
=
=
3.6 Hz), 27.2 (dd, 1JC,P = 133.9, JC,P = 16.1 Hz), 31.8 (dd, 1JC,P
3
General Procedure for the Deprotection of Substituted Heteroaryl-
phosphinoylphosphonates Using Trimethylsilyl Bromide: Into a 50-
mL three-necked flask were introduced 13a, 13d, or 13f (1 mmol)
and dry dichloromethane (10 mL). The mixture was cooled in an
ice bath, and trimethylsilyl bromide (1.9 mL, 15 mmol) was added.
The reaction mixture was stirred at room temperature for 14 h and
then concentrated to dryness under vacuum. Finally, methanol
(10 mL) was poured into the flask, and the resulting mixture was
stirred at room temperature for 2 h and concentrated again under
vacuum. Purification was not required for these compounds.
3
2
102.4, JC,P = 16.1 Hz), 60.4 (d, JC,P = 5.8 Hz), 124.0 (s), 144.7
(d, JC,P = 19.8 Hz), 169.1 (d, JC,P = 142.7 Hz) ppm. HRMS
3
1
(ESI): calcd. for C8H16NO5P2S 300.0224; found 300.0228.
Dilithium Compound 14e: Yellow solid (123 mg, 93%). 31P NMR
4
4
(161.97 MHz, D2O): δ = 27.47 (d, JP,P = 7.6 Hz), 28.16 (d, JP,P
=
=
7.6 Hz) ppm. 1H NMR (400.13 MHz, D2O): δ = 1.06 (t, JH,H
3
7.0 Hz, 3 H), 1.51–1.57 (m, 4 H), 1.87–1.95 (m, 2 H, CH2-3), 3.72
3
4
3
4
(qu, JH,H = JH,P = 7.0 Hz, 2 H), 7.46 (td, JH,H = 5.1 Hz, JH,P
= 2.9 Hz, 1 H), 8.75 (d, JH,H = 5.1 Hz, 2 H) ppm. 13C NMR
3
3
2
(100.61 MHz, D2O): δ = 15.8 (d, JC,P = 5.8 Hz), 16.6 (t, JC,P
=
2.9 Hz), 27.4 (dd, 1JC,P = 133.2 Hz, 3JC,P = 16.1 Hz), 30.1 (dd, 1JC,P
3-(Hydroxy-2-pyridylphosphinoyl)propylphosphonic Acid (6a): Yel-
low oil (251 mg, 95%). 31P NMR (161.97 MHz, D2O): δ = 26.73
= 99.5 Hz, 3JC,P = 17.6 Hz), 60.4 (d, 2JC,P = 5.1 Hz), 122.0 (d, 4JC,P
4
4
(d, JP,P = 5.9 Hz), 32.84 (d, JP,P = 5.9 Hz) ppm. 1H NMR
3
1
=
2.9 Hz), 156.8 (d, JC,P = 12.4 Hz), 168.7 (d, JC,P =
(400.13 MHz, D2O): δ = 1.54–1.74 (m, 4 H), 1.83–1.91 (m, 2 H),
172.7 Hz) ppm. HRMS (ESI): calcd. for C9H17N2O5P2 295.0613;
found 295.0601.
3
8.00 (t, 3JH,H = 6.0 Hz, 1 H), 8.15 (t, JH,H = 6.0 Hz, 1 H), 8.53 (t,
3
3JH,H = 7.72 Hz, 1 H), 8.61 (d, JH,H = 6.0 Hz, 1 H) ppm. 13C
2
NMR (100.61 MHz, D2O): δ = 18.0 (t, JC,P = 2.9 Hz), 29.4 (dd, Supporting Information (see footnote on the first page of this arti-
1JC,P = 133.9 Hz, 3JC,P = 16.8 Hz), 33.3 (dd, 1JC,P = 103.9 Hz, 3JC,P
cle): Characterization data and copies of 31P, 1H, and 13C NMR
spectra and MS and HRMS spectra for all compounds. Copies of
4
2
= 15.4 Hz), 131.2 (d, JC,P = 1.5 Hz), 132.5 (d, JC,P = 10.2 Hz),
3
3
1
1
144.8 (d, JC,P = 5.1 Hz), 149.5 (d, JC,P = 6.6 Hz), 153.5 (d, JC,P
the H and 13C NMR spectra.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
D. Virieux et al.
FULL PAPER
[9] a) K. Bravo-Altamirano, Z. Huang, J.-L. Montchamp, Tetrahe-
dron 2005, 61, 6315–6329; b) K. Bravo-Altamirano, J.-L.
Montchamp, Org. Lett. 2006, 8, 4169–4171; c) K. Bravo-Alta-
mirano, J.-L. Montchamp, Tetrahedron Lett. 2007, 48, 5755–
5759; d) L. Coudray, I. Abrunhosa-Thomas, J.-L. Montchamp,
Tetrahedron Lett. 2007, 48, 6505–6508; e) S. Deprele, J.-L.
Montchamp, J. Am. Chem. Soc. 2002, 124, 9386–9387; f) Q.
Xu, L.-B. Han, Org. Lett. 2006, 8, 2099–2101.
Acknowledgments
This research was supported in part by a grant from Bayer Crop-
Science and from the Agence Nationale de la Recherche et de la
Technologie (ANRT).
[1] For reviews on isoprenoid metabolism, see: a) J. de Ruyck, J.
Wouters, C. D. Poulter, Curr. Enzyme Inhib. 2011, 7, 79–95; b)
C. Obiol-Pardo, J. Rubio-Martinez, S. Imperial, Curr. Med.
Chem. 2011, 18, 1325–1338; c) A. J. Wiemer, C.-H. Hsiao, D. F.
Wiemer, Curr. Top. Med. Chem. 2010, 10, 1858–1871; d) D.
Ganjewala, S. Kumar, R. Luthra, Curr. Issues Mol. Biol.
(Suppl. 1) 2009, 11, i35–i45; e) N. Singh, G. Cheve, M. A.
Avery, C. R. McCurdy, Curr. Pharm. Des. 2007, 13, 1161–1177;
f) P. J. Proteau, Bioorg. Chem. 2004, 32, 483–493.
[10] S. Deprele, J.-L. Montchamp, J. Org. Chem. 2001, 66, 6745–
6755.
[11] a) H.-J. Cristau, A. Herve, D. Virieux, Tetrahedron 2004, 60,
877–884; b) J.-L. Pirat, J. Monbrun, D. Virieux, J.-N. Volle, M.
Tillard, H.-J. Cristau, J. Org. Chem. 2005, 70, 7035–7041.
[12] a) P. Majewska, P. Kafarski, B. Lejczak, Tetrahedron: Asym-
metry 2006, 17, 2870–2875; b) F. Texier-Boullet, A. Foucaud,
Synthesis 1982, 165–166; c) F. Texier-Boullet, M. Lequitte, Tet-
rahedron Lett. 1986, 27, 3515–3516.
[2] For recent papers on the synthesis of fosmidomycin analogues,
see: a) C. T. Behrendt, A. Kunfermann, V. Illarionova, A. Ma-
[13] M. Tao, R. Bihovsky, G. J. Wells, J. P. Mallamo, J. Med. Chem.
1998, 41, 3912–3916.
theeussen, M. K. Pein, T. Graewert, J. Kaiser, A. Bacher, W. [14] P. P. Giannousis, P. A. Bartlett, J. Med. Chem. 1987, 30, 1603–
Eisenreich, B. Illarionov, M. Fischer, L. Maes, M. Groll, T.
Kurz, J. Med. Chem. 2011, 54, 6796–6802; b) M. Andaloussi,
M. Lindh, C. Bjoerkelid, S. Suresh, A. Wieckowska, H. Iyer,
A. Karlen, M. Larhed, Bioorg. Med. Chem. Lett. 2011, 21,
5403–5407; c) M. Andaloussi, L. M. Henriksson, A. Wieckow-
ska, M. Lindh, C. Bjorkelid, A. M. Larsson, S. Suresh, H. Iyer,
B. R. Srinivasa, T. Bergfors, T. Unge, S. L. Mowbray, M.
Larhed, T. A. Jones, A. Karlen, J. Med. Chem. 2011, 54, 4964–
4976; d) L. Deng, J. Diao, P. Chen, V. Pujari, Y. Yao, G. Cheng,
D. Crick, B. V. V. Prasad, Y. Song, J. Med. Chem. 2011, 54,
4721–4734.
1609.
[15] K. S. Bharti, S. K. Singh, Pharmacia Lettre 2009, 1, 39–51.
[16] For reviews on siderophores, see: a) A. du Moulinet d’Hardem-
are, G. Serratrice, J.-L. Pierre, Mini-Rev. Org. Chem. 2010, 7,
125–133; b) A. Butler, R. M. Theisen, Coord. Chem. Rev. 2010,
254, 288–296.
[17] For the pioneering work that was accomplished by Hirao et
al., see: a) T. Hirao, T. Masanuga, Y. Ohshiro, T. Agawa, Tetra-
hedron Lett. 1980, 21, 3595–3598; b) T. Hirao, T. Masanuga,
Y. Ohshiro, T. Agawa, Synthesis 1981, 56; c) T. Hirao, T. Mas-
anuga, N. Yamada, Y. Ohshiro, T. Agawa, Bull. Chem. Soc.
Jpn. 1982, 55, 909–913.
[18] a) J.-L. Pirat, J. Monbrun, D. Virieux, H.-J. Cristau, Tetrahe-
dron 2005, 61, 7029–7036; b) G. P. Luke, W. C. Shakespeare,
Synth. Commun. 2002, 32, 2951–2957; c) Y. Xu, J. Zhang, J.
Chem. Soc., Chem. Commun. 1986, 1606; d) J. Zhang, Y. Xu,
G. Huang, H. Guo, Tetrahedron Lett. 1988, 29, 1955–1958.
[19] P.-A. Jaffrès, N. Bar, D. Villemin, J. Chem. Soc. Perkin Trans.
1 1998, 2083–2089.
[20] a) T. Hayashi, M. Konishi, Y. Kobori, M. Kumada, T. Higuchi,
K. Hirotsu, J. Am. Chem. Soc. 1984, 106, 158–163; b) J. M.
Brown, P. J. Guiry, Inorg. Chim. Acta 1994, 220, 249–259; c)
M. Rottländer, P. Knochel, J. Org. Chem. 1998, 63, 203–208.
[21] For similar results on activated chloroarenes published, during
the course of our study, by J.-L. Montchamp, see: E. L. Deal,
C. Petit, J.-L. Montchamp, Org. Lett. 2011, 13, 3270–3273.
[22] a) P. Shahgaldian, A. W. Coleman, V. I. Kalchenko, Tetrahe-
dron Lett. 2001, 42, 577–579; b) M. C. Allen, W. Fuhrer, B.
Tuck, R. Wade, J. M. Wood, J. Med. Chem. 1989, 32, 1652–
1661; c) M. Morr, C. Kakoschke, L. Ernst, Tetrahedron Lett.
2001, 42, 8841–8843.
[3] A. Mac Sweeney, R. Lange, A. D’Arcy, A. Douangamath, J.-
P. Surivet, C. Oefner, J. Biomol. Chem. 2005, 345, 115–127.
[4] a) J. W. Munos, X. Pu, S. O. Mansoorabadi, H. J. Kim, H.-W.
Liu, J. Am. Chem. Soc. 2009, 131, 2048–2049; b) U. Wong, R. J.
Cox, Angew. Chem. 2007, 119, 5014; Angew. Chem. Int. Ed.
2007, 46, 4926–4929; c) A. Mac Sweeney, R. Lange, R. P. M.
Fernandes, H. Schulz, G. E. Dale, A. Douangamath, P. J. Pro-
teau, C. Oefner, J. Mol. Biol. 2005, 345, 115–127; d) A. Argy-
rou, J. S. Blanchard, Biochemistry 2004, 43, 4375–4387; e) K.
Reuter, S. Sanderbrand, H. Jomaa, J. Wiesner, I. Steinbrecher,
E. Beck, M. Hintz, G. Klebe, M. T. Stubbs, J. Biol. Chem. 2002,
277, 5378–5384.
[5] For a review on phosphorus-based inhibitors of MMP, see a)
A. Veerendhar, R. Reich, E. Breuer, C. R. Chim. 2010, 13,
1191–1202.
[6] A. Mucha, P. Kafarski, Ł. Berlicki, J. Med. Chem. 2011, 54,
5955–5980.
[7] Fosmidomycin analogues were docked in the enzyme using the
Discovery Studio program, from Accelrys, version 2.0.
[8] a) G. T. Shechkov, I. A. Pevneva, O. A. Meshkova, Russ. J.
Appl. Chem. 2003, 76, 1354–1355; b) A. Kers, I. Kers, J. Stawin-
ski, M. Sobkowski, A. Kraszewski, Tetrahedron 1996, 52,
9931–9944; c) J. Stawinski, M. Thelin, E. Westman, R. Zain, J.
Org. Chem. 1990, 55, 3503–3506.
[23] A. Baceiredo, G. Bertrand, P. Mazerolles, J.-P. Majoral, J.
Chem. Soc., Chem. Commun. 1981, 1197–1198.
Received: February 22, 2012
Published Online: ᭿
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20210
/KAP1
Date: 08-05-12 09:22:34
Pages: 13
Fosmidomycin Analogues
Enzyme Inhibitors
S. Montel, C. Midrier, J.-N. Volle,
R. Braun, K. Haaf, L. Willms, J.-L. Pirat,
D. Virieux* ..................................... 1–13
Functionalized
Phosphanyl-Phosphonic
Acids as Unusual Complexing Units as
Analogues of Fosmidomycin
Fosmidomycin (1a) and FR-90098 are po-
tent inhibitors of 1-deoxy-d-xylulose-5-
phosphate reductoisomerase (DXR). The
replacement of the hydroxamic acid by
functionalized phosphinic acids led to four
types of targets which could act as ana-
logues of fosmidomycin.
Keywords: Synthetic methods / Natural
products / Enzymes / Inhibitors / Phos-
phorus / Palladium / Arylation
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
13