Synthesis and biological evaluation of α-hydroxyalkylphosphonates as new antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2013.12.002

A set of α-quaternary 3-chloro-1-hydroxyalkylphosphonates, analogues of fosfomycin and fosfonochlorin, some of which are new compounds, was synthesized. The compounds were screened for bioactivity against several clinical and standard microbial isolates. Some were found to have moderate activity. The activity was higher with phenyl protection of the phosphoryl ester groups and α-phenyl substitution. Compound 11 was as effective or more potent than fosfomycin or chloramphenicol against several Gram-negative bacteria as well as against some Gram-positive ones.

Full text of DOI:10.1016/j.bmcl.2013.12.002

Bioorganic & Medicinal Chemistry Letters 24 (2014) 49–53
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of a-hydroxyalkylphosphonates
as new antimicrobial agents
a,
b
b
Ana Maria Faísca Phillips a, , Maria Teresa Barros , Marta Pacheco , Ricardo Dias
⇑
⇑
a Department of Chemistry, CQFB-REQUIMTE, Faculty of Sciences and Technology, Universidade Nova de Lisboa, Campus de Caparica, Quinta da Torre, 2829-516 Caparica, Portugal
b Microbiology and Biotechnology Laboratory, Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências, Universidade de Lisboa, Campo Grande,
1749-016 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
A set of a-quaternary 3-chloro-1-hydroxyalkylphosphonates, analogues of fosfomycin and fosfonochlo-
rin, some of which are new compounds, was synthesized. The compounds were screened for bioactivity
against several clinical and standard microbial isolates. Some were found to have moderate activity. The
Received 4 November 2013
Revised 29 November 2013
Accepted 1 December 2013
Available online 8 December 2013
activity was higher with phenyl protection of the phosphoryl ester groups and
a-phenyl substitution.
Compound 11 was as effective or more potent than fosfomycin or chloramphenicol against several
Gram-negative bacteria as well as against some Gram-positive ones.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Phosphonates
Antimicrobial activity
Clinical isolates
Gram-positive
Gram-negative
Antibiotics are in great demand. Although many successes have
been achieved in the fight against infectious diseases in the last cen-
tury, the continuous development of resistance by bacteria to the
current antibiotics, and even thedevelopment of multidrugresistant
strains, has left us with a ‘rather bare antibiotic cupboard to meet the
challenges of new outbreaks’.1 Bacterial infections are still a major
cause of death in the developing world. Another problem is resistant
bacteria from hospitals, which cause ‘community-acquired’ infec-
tions, difficult to treat, particularly in immuno-compromised pa-
tients. These resistant bacteria have also acquired toxins that make
them more virulent. Examples are Gram-positive bacteria, like
Staphylococcus aureus and Enterococcus spp., which frequently dis-
play multidrug resistance,2 and Gram-negative Stenotrophomonas
maltophilia. Drug resistance develops as a result of gene mutations,
rearrangements and genetic transfer between different bacteria.3
These are serious problems to populations and to public health sys-
tems due to the morbidity and mortality they cause, and the costs re-
lated to the implementation of effective control measures, and led
the World Health Organization to select ’antimicrobial resistance’
as the theme for World Health Day 2011.
with a broad spectrum of activity, used mainly for the treatment of
uncomplicated urinary tract and gastrointestinal infections.4 Recent
studies showed its potentialfor the treatmentof mutidrug-resistant,
includingextended-spectrumb-lactamase(ESBL)producingEntero-
bacteriaceae infections5 like those caused by Escherichia coli and
Klebsiella pneumoniae, and other Gram-negative species such as
Pseudomonas aeruginosa and Acinetobacter baumannii.6,7 In fact fos-
fomycin is one of the very few antibiotics presently available to treat
Gram-negative infections,8 besides colistin and the new tigecycline
and doripenem.4 Fosfomycin acts by inactivating the enzyme UDP-
N-acetylglucosamine enolpyruvyl transferase (Mur A), thereby
irreversibly blocking condensation of uridine diphosphate-N-ace-
tylglucosamine with phosphoenolpyruvate, one of the first steps in
the peptidoglycan bacterial cell wall synthesis. Normally it is used
together with another antibiotic to prevent the development of
resistance, and it is compatible to many.
We have been interested in the chemistry of phosphonic acid
derivatives for the past few years.9 Many compounds of this class
are biologically active, due to their structural similarity to phos-
phates and carboxylates, competing with them for enzyme binding
sites.10 Examples of other potent phosphonate antibiotics are
fosmidomycin, which is also a potent antimalarial, plumbemycin
A and fosfonochlorin, an antibiotic with spheroplast-forming activ-
ity isolated from cultures of Fusarium sp., moderately active against
some species of Gram-negative bacteria (Fig. 1).11
The development of effective antimicrobial control measures in-
volves both a search for novel compounds and finding new uses for
older drugs. One revival is fosfomycin, a phosphonic acid derivative
⇑
Corresponding authors. Tel./fax: +351 212948300.
E-mail addresses: amfp@fct.unl.pt, ana.faisca@fct.unl.pt (A.M. Faísca Phillips),
Inspired by the structure of fosfomycin, we decided to synthe-
size analogues that could have antimicrobial activity. It is known
mtb@fct.unl.pt (M.T. Barros).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.002

50
A. M. Faísca Phillips et al. / Bioorg. Med. Chem. Lett. 24 (2014) 49–53
O
P
We chose two different types of ester protecting groups: cyclic
O
P
OH
N
H3C
H
phosphonate esters, which are usually more stable than the analo-
gous alkyl esters, and phenyl phosphonate esters which are much
more labile.17,20 The two series of hydroxyphosphonates to be
screened were prepared as shown in Schemes 1 and 2.
For the phosphonates shown in Scheme 1, the intermediate
cyclic phosphite ester 1 needed was obtained via the reaction of
2,2-dimethyl-1,3-propanediol with phosphorus trichloride in the
OH
OH
HO
HO
OH
H
H
O
O
Fosfomycin
Fosmidomycin
O
P
R1O
HO
R1O
O
O
P
O
OH
H
N
P
OH
presence of ethanol, according to
a previously published
HO
HO
Ala
O
N
H
Cl
Cl
procedure.21 Hydroxyphosphonates 2–6 were obtained after the
modified Pudovik reaction (Scheme 1). Diphenyl phosphite is com-
mercially available, and with it hydroxyphosphonates 8–12 could
be synthesized (Scheme 2). 2-Chloroindanone, needed for the syn-
thesis of 12, was obtained via another organocatalyzed reaction, a
O
O
R2
R3
OH
Plumbemycin A
Fosfonochlorin
A
Figure 1. Phosphonate antibiotics.
thiourea-catalyzed
a-chlorination, using N-chlorosuccinimide as
the halogen source.22 To the best of our knowledge, phosphonates
9, 11 and 12 have not been previously described in the literature.23
In the synthesis of compounds 9, 11 and 12, the desired product
was obtained as the major product, together with small amounts of
enolphosphate, as determined by 31P NMR spectroscopy. In each
case there was also usually, in addition, an extra signal at
d = 128.5 ppm, due to unreacted starting material in the phosphite
form (<5%).24 Phosphonates 9 and 12 were obtained as mixtures of
diastereoisomers in approximately a 90:10 ratio. The major diaste-
reoisomers were isolated by chromatography on silica gel and
subsequently recrystallized. Their structures were established by
one- and two-dimensional NMR spectroscopic techniques and by
infrared spectroscopy. Their composition was confirmed by ele-
mental analysis. In the case of cyclopentanol derivatives 9 and
12, NOESY experiments provided some information (included in
the Supplementary data section). C-1 is quaternary and the hydro-
xyl proton did not appear as an independent signal in the spectrum
showing coupling to the C-2 proton. It appears as a very broad sin-
glet in the spectra of most of the compounds in these series. The
nearest protons which could show cross peaks with H-2 and hence
help to establish the stereochemistry at C-2 are the aromatic pro-
tons on the phosphorus ester substituents. They also showed no
cross peaks with H-2, but this fact cannot be taken unambiguosly
that the enzymes that cause resistance to fosfomycin, namely, Fos
A, Fos B, and Fos X, function by nucleophilic attack at the carbon
atom
carbon atom, reaction at this position would become more difficult,
and interesting biological activity may result. We recently
developed an organocatalyzed method for the synthesis of
a
to phosphorus.12 If this centre were to be a quaternary
b-chloro-
structurally related to fosfonochlorin.13 There are existing exam-
ples of biologically active -hydroxyphosphonic acids which are
enzymes inhibitors, but not of biologically active -quaternary
b-chloro-
-hydroxyphosphonates.13 We produced a set of these
a-quaternary hydroxyphosphonates A, which are also
a
a
a
compounds to screen for potential bioactivity and for structure-
activity relationship studies. In this paper we report the synthesis
and characterization of some new phosphonates, not previously
described in the literature, and our results on the evaluation of
the full set for potential antimicrobial activity.
The synthesis of the required
a-hydroxyphosphonates was
based on a method recently developed by us,13 which involves
an organocatalyzed regioselective modified Pudovik reaction be-
tween a dialkylphosphite and a
a
-haloketone.14,15 This reaction
may be carried out under mild conditions using catalytic amounts
of quinine in the presence of a stoichiometric base such as proton-
sponge or pyridine.13 When these conditions are used, b-chloro-
a-
hydroxyphosphonates are obtained. The reaction is compatible
with aliphatic, cyclic or aromatic -haloketones. Since phosphonic
a
acids are negatively charged at nearly all physiological pH values,16
compounds bearing these groups are very polar. High polarity can
be a set back in a drug, preventing efficient delivery to target or-
gans, since highly ionized species do not pass readily across muco-
sal and cellular membranes. The volume of distribution and
bioavailability will be relatively low. In drugs, phosphonates and
phosphates are usually derivatized as neutral esters that can break
down in the body to release the parent drug, since this modifica-
tion alters membrane permeability and improves oral (GI perme-
ability), brain, tumour and cellular delivery. A few studies have
shown the influence of the nature of the phosphonate ester groups
on drug delivery and bioavailability. For example, the acyclic
nucleotide analogue 9-[2-(phosphonomethoxy)ethoxy]adenine, a
potent and selective inhibitor of the human immunodeficiency
virus-1 (HIV-1) and immunodeficiency virus-2 (HIV-2), has
very low bioavailability.17 Derivatization as bis[pivaloyloxy)
methyl]ester or diphenyl ester provide good oral bioavailability.17
A similar effect of the phenyl group was shown in Adefovir, 9-[2-
(phosphonomethoxy)ethyl]adenine, a nucleotide analogue used
clinically to treat chronic hepatitis B virus infection. It also
enhanced the in vitro activity against HSV-2 (G-strain) when com-
O
EtOH
r.t.
PCl3
O
O
P
H
OH OH
1
O
Cl
(Ar)R
quinine / pyridine or proton sponge
toluene, r.t.
O
O
O
O
O
O
P
P
HO
Cl
O
Cl
HO
Me
2
3
O
O
O
O
O
O
O
O
P
P
P
Cl
Cl
Cl
Me
HO
HO
HO
pared with the unprotected drug (IC50 = 77 lM vs 119 lM in the
unprotected drug).18 With the endopeptidase inhibitor CGS
25462, diphenyl ester derivatization provided a 200-fold increase
of the active drug in the plasma above its IC50 value.19
4
5
Cl
6
Scheme 1. Synthesis of cyclic alkylphosphonate esters.

A. M. Faísca Phillips et al. / Bioorg. Med. Chem. Lett. 24 (2014) 49–53
51
O
OMe
PhO
H
O
N
PhO
P
H
S
C
O
Cl
N
OH
H2N
NH2
Cl
O
O
Me(Ph)
24 oC, 2,5 h
Ref. 22
7
N
pyridine, rt or
proton sponge, 0 oC
toluene
pyridine
toluene, rt
18 h
O
O
pyridine
toluene, rt
15-18 h
Ref. 13
Cl
or
Cl
4-Cl-C6H4COCl
PhO
PhO
PhO
PhO
PhO
PhO
PhO
PhO
O
O
O
O
O
OH
PhO
PhO
P
P
P
P
P
HO
Cl
Cl
Cl
Cl
HO
Me
Cl
Cl
OH
OH
11
12
9
8
10
Scheme 2. Synthesis of diphenyl alkylphosphonate esters.
to imply that they occupy the region in space on the face opposite
to H-2, because they could be simply too far away to be detected.
With 12 a cross peak between one of the H-3 protons and the hy-
droxyl group suggests a correlation, which being absent with H-2,
must imply that H-2 and the hydroxyl group occupy the space on
opposite faces of the ring. In cyclopentanones the lowest energy
conformation is the envelope, and when there is a substituent at
Gram-negative bacteria Escherichia coli BW54, E. coli BW55, Acinec-
tobacter haemolyticus BW62, Stenotrophomonas maltophilia D457R
and Pseudomonas aeruginosa PAO1, and the Gram-positive Bacillus
cereus ATCC 11778, Staphylococcus aureus ATCC 29213 and S. aur-
eus BW61. For comparison, the activity of the standard drugs fosfo-
mycin, ceftriaxone, ciprofloxacin and chloramphenicol was
evaluated under the same conditions. A preliminary screening
was carried out using the disc diffusion method, according to the
Clinical Laboratory Standards Institute (CLSI) Guidelines,26,27 and
the results are presented in Table 1. All the hydroxyphosphonates
tested, except compound 2, exhibited some antimicrobial activity.
the
a
-position two situations are possible: B and C (Fig. 2).25 The
reacting nucleophile can then approach from side a or b in each
case. However, envelope B, with the chloro substituent pseudo-
equatorial, should be lower in energy, and it is the conformation
considered when a prediction of the stereochemical outcome of
reactions is made. Approach of the nucleophile is expected, from
empirical observations in other nucleophilic additions to carbonyl
compounds, to take place at an angle of ꢀ110° (the Bürgi–Dunitz
trajectory), that is via path a. This approach gives rise to a product
in which Cl and OH groups are trans. However, when there are with
The measurement of the zones of growth inhibition for 10 lg of
each compound showed that the most active compounds were
hydroxyphosphonates 8, 10, 11 and 12, which inhibited the growth
of Gram-negative as well as Gram-positive bacteria. These com-
pounds were selected for further screening. They have in common
the diphenyl ester-protecting group, which suggests that the pres-
ence of this group may be important for activity. Compound 9,
which has the same protecting group but was less active, was also
selected, as well as 5, a cyclic ester which was active against E. coli
BW55, an ESBL-producing E. coli.
The minimum concentrations of each compound required to in-
hibit growth (MIC values) and the minimum bactericidal concentra-
tions of each compound, that is the concentration required to kill
each pathogen (MBC values) were then determined for the chosen
compounds as well as for a set of standard drugs: fosfomycin, ceftri-
axone, ciprofloxacin and chloramphenicol. They represent the epox-
yphosphonate, thecephalosporin, and thefluoroquinoloneclassesof
drugs, and chloramphenicol stands as a broad spectrum bacterial
protein synthesis inhibitor. The strain S. Aureus ATCC 29213 was
used for quality control. The results are presented in Tables 2–4.
MIC and MBC values were determined according to CLSI speci-
fications.26,27 The most active compound was 11, with MIC values
very bulky substituents at the
is very bulky, which is the present case, unfavourable steric inter-
actions between the -substituent and the nucleophile will favour
a-position, or when the nucleophile
a
nucleophile approach along path b [23], giving rise to a cis product.
Hence we predict that in our products 9 and 12 the stereochemis-
try is one in which the Cl and OH groups are cis. All the hydrox-
yphosphonates used in this study were crystalline compounds
that could be obtained in a very pure state after chromatography
and recrystallization.
The antimicrobial activity of the compounds prepared was eval-
uated in vitro against standard and clinically isolated strains of the
Small Nu
a
H
Nu
H
O
H
Cl
a
Cl
H
Table 1
b
H
H
Zone of growth inhibition (mm) of the hydroxyalkylphosphonates against different
Gram-negative and Gram-positive clinical and other isolates
b
O
Nu
Bulky Nu
Strain
Compounda
B
C
Lower energy conformation
Higher energy conformation
2
3
4
5
6
8
9
10
11
12
Nu = 7
Gram-negative
E. coli BW54
E. coli BW55
A. haemolyticus BW62
S. maltophilia D457R
P. aeruginosa PAO1
O
Path b
—
—
—
—
—
—
—
—
6
—
—
—
—
6
—
7
—
—
—
—
—
—
7
8
7
8
—
7
—
—
—
—
—
9
10
8
7
7
9
10
7
11
10
—
8
—
—
9
P
O
H
O
PhO
PhO
PhO
PhO
O
O
7
P
P
OH
Cl
OH
Cl
6
—
Gram-positive
B. cereus ATCC 11778
S. aureus ATCC 29213
—
—
—
—
7
—
—
—
—
—
12
9
—
8
7
—
9
9
—
5
9
12
a
10 lg of each compound was used; —, no bioactivity observed.
Figure 2. The lowest energy conformations of 9.

52
A. M. Faísca Phillips et al. / Bioorg. Med. Chem. Lett. 24 (2014) 49–53
Table 2
Compounds 5, 10 and 11 have in common an aromatic substituent
at the -position.
Hydroxyphosphonate 10 displays bactericidal activity at lower
concentrations against all pathogens tested (32–64 g/mL, i.e.,
83–165 M), followed by 11 (32–128 g/mL, i.e., 76–304 M).
Minimum inhibitory concentration (lg/mL) of the hydroxyalkylphosphonates against
different Gram-negative and Gram-positive clinical and reference isolates
a
Strain
Compound
l
l
l
l
5
8
9
10
11
12
In comparison with the standard drugs, 10 and 11 were either
more or equally bactericidal than chloramphenicol, and in most
cases better than fosfomycin. In fact, hydroxyphosphonate 11
showed better inhibitory activity than fosfomycin against several
Gram-negative strains. Fosfomycin resistant S. maltophilia D457R
has the multidrug efflux system SmeDEF over-expressed.29 It is
possible that 11 blocks the activity of the multidrug efflux system
SmeDEF and/or it’s activity is not impaired by SmeDEF overex-
pression, and if so, the use of this compound as an additive might
restore the activity of other antimicrobial agents towards Gram-
negative bacteria. Although at present there are no efflux inhibi-
tors in clinical use, they are the subject of active research, either
in clinical phases of development, or are being used to determine
the efflux prevalence in clinical isolates. The possibility of 12
Gram-negative
E. coli BW54
E. coli BW55
A. haemolyticus BW62
S. maltophilia D457R
P. aeruginosa PAO1
64
64
64
64
128
64
64
128
64
128
128
128
128
256
64
64
64
64
64
64
32
64
32
128
128
128
128
128
128
128
Gram-positive
B. cereus ATCC 11778
S. aureus ATCC 29213
S. aureus BW61
64
64
64
64
128
128
128
256
256
64
64
64
32
32
32
128
256
256
Table 3
Minimum bactericidal concentration
against different Gram-negative and Gram-positive clinical and reference isolates
(lg/mL) of the hydroxyalkylphosphonates
being an efflux inhibitor will be
investigations.
a subject of our future
Strain
Compound
In summary,
a set of a-quaternary 3-chloro-2-hydrox-
5
8
9
10
11
12
yalkylphosphonates was prepared, some of which have not been
described previously. The compounds were screened for antimi-
crobial activity and some were found to be moderate growth inhib-
itors and bactericides against a range of clinical and standard
isolates of pathogenic bacteria. Compound 11 was more active
than fosfomycin or chloramphenicol against several Gram-nega-
tive and also some Gram-positive isolates. Phenyl protection of
Gram-negative
E. coli BW54
E. coli BW55
A. haemolyticus BW62
S. maltophilia D457R
P. aeruginosa PAO1
128
128
128
256
128
P256
256
P256
P256
256
256
256
256
256
256
64
64
64
64
64
64
256
256
256
256
256
64
128
64
128
Gram-positive
B. cereus ATCC 11778
S. aureus ATCC 29213
S. aureus BW61
128
128
128
128
P256
256
256
P256
P256
32
64
64
32
64
64
256
256
256
the phosphoryl ester groups and aromatic substitution at the a-po-
sition was found to enhance bioactivity. To the best of our knowl-
edge bioactivity of this class of compounds has not been reported
before. Our studies in this area are continuing.
Table 4
MIC ( g/mL)/MBC (
different Gram-negative and Gram-positive clinical and reference isolates
Acknowledgments
l
lg/mL) of the class representative antimicrobial agents against
This work was financed by National funds through FCT—Fun-
dação para a Ciência e a Tecnologia—project PEst-C/EQB/LA0006/
2011. The NMR spectrometers are part of The National NMR Facil-
ity, supported by Fundação para a Ciência e a Tecnologia (RECI/
BBB-BQB/0230/2012).
Strain
Antimicrobial agenta
FOS
CFX
CIPX
CHLOR
Gram-negative
E. coli BW54
E. coli BW55
A. haemolyticus BW62
S. maltophilia D457R
P. aeruginosa PAO1
32/32
60.5/0.5
32/64
4/4
2/1
128/P256
8/128
128/P256
128/P256
P256/P256
32/128
128/128
256/256
64/64
4/4
4/4
64/128
128/128
4/256
4/4
Supplementary data
Gram-positive
Supplementary data (Experimental protocols, full characteriza-
tion data of compounds 9, 11, and 12 and their NMR and IR spectra
as well as the description and source of the strains used in this
study.) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.bmcl.2013.12.002.
B. cereus ATCC 11778
S. aureus ATCC 29213
S. aureus BW61
32/32
8/64
64/32
32/64
4/4
4/4
4/4
4/4
4/4
0.5/64
8/64
16/128
a
FOS = fosfomycin;
CHLOR = chloramphenicol.
CFX = ceftriaxone;
CIPX = ciproflaxin;
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appearing with increasing frequency in the communities outside.28
For 11 MIC values were in the range of 32–64
against the Gram-negative pathogens, except for P. aeruginosa
PAO1 which was inhibited at 128 g/mL (304 M).
Compounds 10 and 5 were slightly less active than 11, but
showed MIC values of 64 g/mL (165 and 189 M, respectively),
lg/mL (76–152 lM)
l
l
l
l
against all pathogens tested also with the exception of P. aerugin-
osa. These values are within the susceptibility breakpoint, which
is usually regarded to be 64
met with this criterion for a few of the pathogens tested (Table 2).
l
g/mL.5 Hydroxyphosphonate 8 also

A. M. Faísca Phillips et al. / Bioorg. Med. Chem. Lett. 24 (2014) 49–53
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(1.0 mmol) in dry toluene (3 mL) was added quinine (0.10–0.30 mmol) and
the mixture was stirred under argon until the catalyst had dissolved. The base
(proton sponge or pyridine) (1.0 mmol) was added and the mixture was stirred
until clear. The solution was cooled in an ice bath and the
a-chloroketone
13. Barros, M. T.; Faísca Phillips, A. M. Eur. J. Org. Chem., IYC Special Issue: Women
in, Chemistry 2011, 4028.
(1.5 mmol) was added. When the starting material was consumed, HCl (1 M)
was added and the product was extracted with chloroform. The combined
organic extracts were washed with water and the solution was filtered through
anhydrous sodium sulphate. The solvent was removed on a rotary evaporator
to give the crude product as a solid, purified by chromatography (silica gel, 3:1
hex/EtOAc) and recystallized from EtOAc/hexane. Compound 11 was obtained
as white crystals, mp 138–139 °C. 1H NMR (CDCl3): d 4.28 (t, 1 H, JHH = JHP
11.7 Hz), 4.41 (dd, 1 H, JHP 4.8 Hz, JHH 11.7 Hz), 6.86 (d, 2 H, JHH 8.5 Hz), 7.05–
7.25 (m, 6 H), 7.29 (t, 2 H, JHH 7.7 Hz), 7.37 (d, 2 H, JHH 8.4 Hz), 7.64 (dd, 2 H, JHH
2.4, 8.8 Hz) ppm; 13C NMR (CDCl3): d 49.89 (d, JCP 14.9 Hz, CH2), 75.33 (s, Cq),
120.2 (d, JCP 4.3 Hz, CH), 120.5 (d, JCP 4.1 Hz, CH), 125.4 (s, CH), 125.6 (s, CH),
128.0 (d, JCP 4.4 Hz, CH), 128.7 (d, JCP 2.7 Hz, CH), 129.6 (d, JCP 0.7 Hz, CH), 129.8
(d, JCP 0.8 Hz, CH), 134.5 (s), 134.8 (d, JCP 3.6 Hz, Cq), 150.1 (d, JCP 4.9 Hz, Cq),
14. For other organocatalyzed reactions leading to the synthesis of
a-
hydroxyphosphonates, but not to b-chloro- -hydroxyphosphonates see: (a)
a
Mandal, T.; Samanta, S.; Zhao, C.-G. Org. Letts 2007, 9, 943; (b) Kolodyazhnaya,
A. O.; Kukhar, V. P.; Kolodyazhnyi, O. I. Russ. J. Gen. Chem. 2008, 78, 2043; (c)
Liu, J.; Yang, Z.; Wang, Z.; Wang, F.; Chen, X.; Liu, X.; Feng, X.; Su, Z.; Hu, C. J.
Am. Chem. Soc. 2008, 130, 5654; (d) Chen, X.; Wang, J.; Zhu, Y.; Shang, D.; Gao,
B.; Liu, X.; Feng, X.; Su, Z.; Hu, C. A. Chem. Eur. J. 2008, 14, 10896; (e) Wang, F.;
Liu, X.; Cui, X.; Xiong, Y.; Zhou, Y.; Feng, X. Chem. Eur. J. 2009, 15, 589; (f) Jiang,
J.; Chen, X.; Wang, J.; Hui, Y.; Liu, X.; Lin, L.; Feng, X. Org. Biomol. Chem. 2009, 7,
4355; (g) Gondi, V. B.; Hagihara, K.; Rawal, V. H. Angew. Chem. Int. Ed. 2009, 48,
776; (h) Uraguchi, D.; Ito, T.; Nakamura, S.; Ooi, T. Chem. Sci. 2010, 1, 488; (i)
Perera, S.; Naganaboina, V. K.; Wang, L.; Zhang, B.; Guo, Q.; Rout, L.; Zhao, C.-G.
Adv. Synth. Catal. 2011, 353, 1729; (j) Lee, H. J.; Kim, J. H.; Kim, D. Y. Bull. Korean
Chem. Soc. 2011, 32, 785.
150.2 (d, JCP 4.9 Hz, Cq) ppm; 31P NMR (CDCl3): d 11.37 ppm; IR (KBr):
m 3314,
3056, 2948, 1654, 1589, 1489, 1457, 1429, 1402, 1363, 1291, 1238, 1207, 1184,
1161, 1124, 1097, 1073, 1023, 1016, 1007, 991, 973, 948, 913, 825, 777, 761,
722, 686, 619 cmÀ1. Anal. Calcd for C20H17Cl2O4P: C 56.76, H 4.05; found: C
57.18, H 4.08.
15. For a recent review on organocatalysis for the synthesis of phosphonates see:
Faísca Phillips, A. M. Mini-Rev. Org. Chem. 2013, accepted for publication.
16. Krise, J. P.; Stella, V. J. Adv. Drug Deliv. Rev. 1996, 19, 287.
17. Serafinowska, H. T.; Ashton, R. J.; Bailey, S.; Harnden, M. R.; Jackson, S. M.;
Sutton, D. J. Med. Chem. 1995, 38, 1372.
18. Starrett, J. E., Jr; Tortolani, D. R.; Russell, J. R.; Hitchcock, M. J. M.; Whiterock, V.;
Martin, J. C.; Mansuri, M. M. J. Med. Chem. 1994, 37, 1857.
19. De Lombaert, S.; Erion, M. D.; Tan, J.; Blanchard, L.; El-Chehabi, L.; Ghai, R. D.;
Sakane, Y.; Berry, C.; Trapani, A. J. J. Med. Chem. 1994, 37, 498.
24. Abbaraju, S.; Bhanushali, M.; Zhao, C.-G. Tetrahedron 2011, 67, 7479.
25. Smith, M. B. Organic Synthesis, 3rd ed.; Academic Press: New York, 2011.
26. Clinical and Laboratory Standards Institute (CLSI), Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically,
Approved Standards, CLSI Document M7–A7, 7th ed., 2006.
27. Clinical and Laboratory Standards Institute (CLSI), Performance Standards for
Antimicrobial Susceptibility Testing, 17th Informational Supplement, CLSI
Document M100–S17, 2007.
20. Hecker, S. J.; Erion, M. D. J. Med. Chem. 2008, 51, 2328.
21. McConnell, R. L.; Coover, H. W., Jr J. Org. Chem. 1959, 24, 630.
22. Mei, Y.; Bentley, P. A.; Du, J. Tetrahedron Lett. 2008, 49, 3802.
28. Garwood, J. Lab Times 2011, 7, 18.
29. Alonso, A.; Morales, G.; Escalante, R.; Campanario, E.; Sastre, L.; Martinez, J. L. J.
Antimicrob. Chemother. 2004, 53, 432.
23. Representative
procedure
for
diphenyl
[2-chloro-1-hydroxy-1-(4-
chlorophenyl)ethyl]phosphonate (11): To
a
solution of the phosphite