An approach to the synthesis and assignment of the absolute configuration of all enantiomers of ethyl hydroxy(phenyl)methane(P-phenyl)phosphinate

Article abstract of DOI:10.1016/j.tetasy.2006.09.021

Ethyl butyryloxy(phenyl)methane(P-phenyl)phosphinate was hydrolyzed using four bacterial species as biocatalysts. In all cases the reaction was stereoselective and isomers bearing an α-carbon atom with an (S)-configuration were hydrolyzed preferentially.

Full text of DOI:10.1016/j.tetasy.2006.09.021

Tetrahedron: Asymmetry 17 (2006) 2697–2701
An approach to the synthesis and assignment of the
absolute configuration of all enantiomers of
ethyl hydroxy(phenyl)methane(P-phenyl)phosphinate
Paulina Majewska,a,* Paweł Kafarski,a Barbara Lejczak,a Iwona Bryndalb and Tadeusz Lisb
aDepartment of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology,
Wybrzez_e Wyspian´skiego 27, 50-370 Wrocław, Poland
bFaculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383 Wrocław, Poland
Received 7 September 2006; accepted 19 September 2006
Abstract—Ethyl butyryloxy(phenyl)methane(P-phenyl)phosphinate was hydrolyzed using four bacterial species as biocatalysts. In all
cases the reaction was stereoselective and isomers bearing an a-carbon atom with an (S)-configuration were hydrolyzed preferentially.
Also a lack of stereoselectivity toward the phosphorus atom was observed. Hydrolysis of one enantiomeric mixture, namely mixture of
(SP,R) and (RP,S) configuration afforded enantiomerically pure ethyl (RP,S)-hydroxy(phenyl)methane(P-phenyl)phosphinate, configura-
tion of which was established by X-ray crystallography. The observed 1H and 31P NMR chemical shifts of Mosher esters of ethyl
hydroxy(phenyl)methane(P-phenyl)phosphinate were correlated with the configurations of both stereogenic centers of all four
stereoisomers.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
approach by using microbial cells as biocatalysts for the
hydrolysis of ethyl butyryloxy(phenyl)methane(P-phen-
yl)phosphinate. Some efforts were also undertaken to
separate all four stereoisomers of the product—ethyl
hydroxy(phenyl)methane(P-phenyl)phosphinate.
Syntheses of chiral a-hydroxyphosphonates have gathered
considerable attention recently mostly due to their useful-
ness as intermediates for the synthesis of other phosphorus
compounds of variable use.1–4 Hydroxyalkanephosphonic
acids have also received attention because their biological
activity has not been fully explored. However, isolated
examples of their activity include the inhibition of such
important medicinal enzymes as renin5,6 or human immu-
nodeficiency virus (HIV) protease and polymerase.7–9 Far
less data are available about the synthesis of chiral hydroxy-
phosphinates, especially considering chirality at the phos-
phorus atom. The only example of the transfer of
chirality from the carbon to phosphorus atom was
described upon stereoselective lipase-catalyzed acylation
of ethyl (1-hydroxyethyl)phenylphosphinate.10 The same
reaction carried out with the use of other lipases have
shown, however, a lack of stereoselection at the phospho-
rus atom.11 Herein, we have extended the scope of this
2. Results and discussion
2.1. Biotransformations
Racemic ethyl hydroxy(phenyl)methane(P-phenyl)phosph-
inate 1, obtained by the classical addition of ethyl phenyl-
phosphinate to benzaldehyde,12 was converted into ethyl
butyryloxy(phenyl)methane(P-phenyl)phosphinate
2
by
simple acylation with butyryl chloride. The latter was
hydrolyzed using whole cells of four bacterial species
(Table 1). As seen from Table 1, the reaction was stereo-
selective and isomers bearing an a-carbon atom with an
(S)-configuration were hydrolyzed preferentially with a
lack of stereoselectivity toward phosphorus atom (see
also Scheme 1). These results are in a good agreement
with those observed for ethyl (1-hydroxyethyl)phenyl-
phosphinate.11
*
Corresponding author. Tel.: +48 71 320 2597; fax: +48 71 328 4064;
e-mail: paulina.majewska@pwr.wroc.pl
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.09.021

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P. Majewska et al. / Tetrahedron: Asymmetry 17 (2006) 2697–2701
Table 1. Hydrolysis of ethyl butyryloxy(phenyl)methane(P-phenyl)phos-
phinate 2 by microorganisms via Scheme 1
eluent. Efforts to obtain the second diastereomeric mixture,
namely the mixture of (RP,R)-2 and (SP,S)-2, were
unsuccessful.
Microorganism
Time
[h]
Conversion
[%]
ee of alcohol
[%]
The diastereomeric mixture of (SP,R)-2 and (RP,S)-2 was
then hydrolyzed using B. subtilis as the biocatalyst (17 h;
yield 37%; ee 87%) resulting, after HPLC chromatography
(preparative C18 column), in pure (RP,S)-1 {[a]D = +2.8 (c
1.67, CH3Cl, 23 ꢁC)}. Crystallization of this compound
from methylene chloride/n-hexane mixture, carried out in
sealed capillary, gave crystals suitable for crystallographic
studies. The absolute configuration of this compound was
determined by X-ray studies.
(RP,R) (SP,R) (SP,S) (RP,S)
(SP,S) (RP,S)
Bacillus subtilis
24
72
48
72
90
168
48
94
49
82
33
79
44
68
30
41
50
77
16
76
67
63
14
27
90
24
4
19
51
11
62
31
90
31
33
39
66
28
72
38
Acinetobacter baumannii
Serratia liquefaciens
Pseudomonas aeruginosa
2.3. Determination of the absolute configuration of (RP,S)-1
by X-ray crystallography
O
P
O
The absolute configuration of compound 1, obtained via
biocatalytic hydrolysis of a pure mixture of diastereoiso-
mers of compound 2, was determined with the Flack
parameter refining to a value of 0.01(3). As clearly seen
from Figure 1, the configuration of the obtained compound
1 was determined as (RP,S). This assignment was then used
to determine the absolute configuration of the remaining
stereoisomers by means of NMR spectroscopy.
O
EtO
H
Ph
Ph
2
O
O
O
OH
P
P
+
+
O
O
Ph
H
EtO
Ph
Ph
EtO
Ph
H
(
SP,
R)-2
(
RP
,S
)-1
O
O
O
OH
Ph
P
P
Ph
EtO
EtO
Ph
H
Ph
H
(RP,R
)-2
(SP,S
)-1
Scheme 1. Stereochemical course of microbial hydrolysis of racemic ethyl
butyryloxy(phenyl)methane(P-phenyl)phosphinate 2.
The best results were obtained with cells of Bacillus subtilis
after 24 h reaction time. Although both enantiomeric mix-
tures were converted in only 50%, the enantiomeric excess
of the resulting hydroxyphosphinate 1 was satisfactory.
Increasing the reaction time resulted in the elevation of
its yield with simultaneous decrease of the stereoselectivity
of the process, which is typical for biotransformations car-
ried out with whole cells.
2.2. Resolution of stereoisomers
Figure 1. Molecular structure of (RP,S)-1 showing the atom-labelling
schemes. Displacement ellipsoids are drawn at the 50% probability level.
When purifying ethyl butyryloxy(phenyl)methane(P-
phenyl)phosphinate by means of column chromatography,
the possibility of the resolution of diastereoisomers, namely
a mixture of (RP,R)-2 and (SP,S)-2 from compounds
(SP,R)-2 and (RP,S)-2, was noticed. This appeared to be
no easy task and we succeeded in only obtaining pure dia-
stereomeric mixture of (SP,R)-2 and (RP,S)-2 in a 10%
yield, when using a silica gel column and mixture of
methylene chloride/n-hexane/ethyl acetate (1:1:0.5 v/v) as
Compound (RP,S)-1 crystallizes from a mixture of methyl-
ene chloride/n-hexane with one independent molecule in
the asymmetric unit (Fig. 1). The molecules are linked by
strong hydrogen bonds of the P@Oꢀ ꢀ ꢀH–O type formed be-
tween phosphinate and hydroxyl moieties of neighboring
molecules to give chains extending along the b axis. Such
chains are linked by weak C–Hꢀ ꢀ ꢀO hydrogen bonds

P. Majewska et al. / Tetrahedron: Asymmetry 17 (2006) 2697–2701
2699
involving phenyl rings and ethyl ester groups. The afore-
mentioned arrangement results in the formation of layers
parallel to the ab plane. Thus, the hydrophilic core formed
by phosphinate fragments is separated by hydrophobic
parts formed by all the hydrophobic fragments of the mole-
cule (Fig. 2).
aromatic ring on the chemical shift of these protons present
in the Mosher acid moiety (see Scheme 2).14
upfield relative to
EtO
O
O
Ph
Ph
CF
Ph
CF
MeO
O
P
MeO
Ph
Ph
EtO
Ph
P
O
3
(R
)
3
(R)
(S)
(R)
H
O
H
O
(
RP
and
SP
,
R
,
R
)-3
(
RP
and
SP
,
S
,
R
)-3
)-3
(
,
R
,
R
)-3
(
,
S
,
R
Scheme 2. Anisotropic effect of the phenyl ring of the phosphinate on
chemical shift of the Mosher acid methoxy protons.
In the final step, a mixture of substrate 2 (all four stereoiso-
mers applied in molar ratio of: (RP,S):(SP,R):(RP,R):
(SP,S) = 4.6:2.8:1:0.6), available from one experiment of
hydrolysis of the 4.6:4.6:1:1 mixture of 2 with B. subtilis,
was hydrolyzed with sulfuric acid in methanol and the
product (a corresponding mixture of four stereoisomers
of 1) acylated with (S)-(+)MTPA-Cl. Considering the gen-
erality of interaction between phenylphosphinate fragment
and the methoxy group in 3, isomers with an (S)-configura-
tion at the a-carbon atom of the phosphinate molecule
should have chemical shifts of methoxy protons upfield
relative to the corresponding (R)-isomers. Therefore, the
observed chemical shifts for the remaining (RP,R,R)-3
and (SP,S,R)-3 are 3.42 and 3.50 ppm, respectively.
Figure 2. Structural alignment of (RP,S)-1 molecules in the crystal
structure.
The same reasoning applies to the 31P NMR spectra. As
shown in Scheme 2, the interaction between the phenyl ring
and phosphinate group is seen for (SP,S,R)-3 and (RP,S,R)-
3 (chemical shifts of 33.00 and 32.80 ppm, respectively)
should be upfield relative to isomers (SP,R,R)-3 and
(RP,R,R)-3 (32.94 and 32.55 ppm, respectively). This is
indeed the fact, which additionally supports proper assign-
2.4. Configurational NMR assignments
NMR is normally used for the determination of absolute
configuration of a-hydroxyphosphonates.1 Since the
Mosher approach is most commonly used for that pur-
pose,13 we have decided to use this approach. In the first
step, pure ethyl (RP,S)-hydroxy(phenyl)methane(P-phenyl)-
phosphinate was esterified with (S)-(+)MTPA-Cl yielding
the ester of (R)-MTPA (compound (RP,S,R)-3), thus
obtaining the standard for further studies.
1
ment made by H NMR.
3. Experimental
3.1. General
In the next step, a non-equimolar mixture of (SP,R)-2 and
(RP,S)-2 (1:0.47; ee = 36%), obtained as the unreacted sub-
strate isolated from the mixture obtained after hydrolysis
of this enantiomeric mixture by B. subtilis, was hydrolyzed
with small amounts of sulfuric acid in methanol (15 mg of
the mixture, three droplets of concentrated sulfuric acid in
3 ml of methanol). This procedure yielded, in a 1:0.47
molar ratio, a mixture of (ee = 36%), which was then
acylated with (S)-(+)MTPA-Cl resulting in a mixture of
compounds (SP,R,R)-3 and (RP,S,R)-3 (molar ratio of
1:0.47) for analysis by means of NMR. The observed chem-
NMR spectra were measured on a Bruker AvanceTM 600 at
1
600.58 MHz for H; 243.12 MHz for 31P and 151.02 MHz
for 13C in CDCl3 or on a Bruker Avance DRX 300 instru-
ment operating at 300.13 MHz for 1H and 121.50 MHz for
31P in CDCl3. Chemical shifts (d) are reported in parts per
1
million and coupling constants (J) are given in Hertz. H
NMR are referenced to internal TMS (d = 0.00), 13C
NMR spectra to the center line of CHCl3 (d = 77.23) and
85% phosphoric acid in H2O for 31P NMR spectra was
used as external reference. Optical rotation was measured
in CHCl3 using polAAr-31 polarimeter (578 nm). All com-
pounds were purified by gradient column chromatography
using Merck Silica Gel 60 (63–230 mesh) or by HPLC
(Varian, Dynamax HPLC Column 250 · 21.4 mm;
MICROSORB 300-10 C18). All materials were purchased
1
ical shifts of the methoxy protons in the H NMR spectra
were 3.39 ppm for (SP,R,R)-3 and 3.43 ppm for (RP,S,R)-3.
This is in good agreement with previous studies and results
from the anisotropic effect of the phenylphosphinate

2700
P. Majewska et al. / Tetrahedron: Asymmetry 17 (2006) 2697–2701
from commercial suppliers: Sigma, Aldrich, Fluka, POCh
and used without further purification.
127.81, 128.41, 128.49, 128.63, 132.64, 132.71, 132.92,
133.48 (aromatic carbons), 172.00 (d, J = 6.9 Hz, C@O).
3.3.2. Mixture of (RP,S)- and (SP,R)-enantiomers. 31P
NMR d (ppm) 34.52; 1H NMR: d (ppm): 0.83 (t,
J = 7.4 Hz, 3H, CH2CH2CH3), 1.25 (t, J = 7.0 Hz, 3H,
OCH2CH3), 1.50–1.58 (m, 2H, CH2CH3), 2.27 (dt,
J = 2.2 Hz, J = 7.4 Hz, 2H, C(O)CH2), 4.00–4.07 (m, 2H,
OCH2), 6.32 (d, J = 10.6 Hz, 1H, CHP), 7.25–7.72 (m,
10H, aromatic protons); 13C NMR d (ppm): 13.63
(CH2CH2CH3), 16.58 (d, J = 6.3 Hz, OCH2CH3), 18.45
(CH2CH2CH3), 36.17 (C(O)CH2), 61.91 (d, J = 6.6 Hz,
OCH2), 72.35 (d, J = 119.1 Hz, CHP), 127.99, 128.02,
128.41 (2C), 128.49, 128.62, 132.65, 132.71, 133.90,
133.37 (aromatic carbons), 171.94 (d, J = 7.5, C@O).
3.2. Synthesis of ethyl hydroxy(phenyl)methane-
(P-phenyl)phosphinate 1
Aluminum oxide (5 g) was mixed with 5 g of potassium
fluoride and powdered in a grinder. Then 20 mmol of ethyl
phenylphosphinate and 20 mmol of the acetic aldehyde was
added into this mixture and left at room temperature for
48 h. After this time, the mixture was eluted by dichloro-
methane. The desired compound 1 was purified by gradient
column chromatography on silica gel using dichlorometh-
ane/ethyl acetate (5:3 v/v) as eluent; Rf (1) = 0.29. This
procedure resulted in the mixture of diastereoisomers
obtained in 1:1 molar ratio with 51% yield.
3.4. Synthesis of Mosher esters
3.2.1. Mixture of (RP,R)- and (SP,S)-isomers. 31P NMR d
(ppm): 39.56; H NMR: d (ppm) 1.32 (t, J = 7.0 Hz, 3H,
OCH3), 3.93–4.18 (m, 2H, OCH2), 5.16 (d, J = 10.4 Hz,
1H, CHP), 7.20–7.64 (m, 10H, aromatic protons); 13C
NMR d (ppm): 16.71 (d, J = 6.1, CH3), 62.09 (OCH2),
73.41 (d, J = 111.3, CHP), 127.18, 127.22, 127.92 (d,
J = 3.1), 128.08, 128.10, 128.25, 132.68 (d, J = 2.2),
132.77, 133.06, 136.58 (aromatic carbons).
Compound 1 of various stereomeric compositions was
acylated according to the literature:13 0.10 mmol of 1 was
dissolved in the mixture composed of dry dichloromethane
(300 ll) and dry pyridine (300 ll), followed by the addition
of 0.14 mmol of (S)-(+)MTPA-Cl. The mixture was left for
3 days at room temperature. An excess of 3-dimethyl-
amino-1-propylamine (0.20 mmol) was then added and
after 5 min at room temperature, the mixture was diluted
with diethyl ether (10 ml), washed by cold dilute HCl
(10 ml) and water (10 ml), and dried over anhydrous mag-
nesium sulfate. After filtration of the drying agent, ether
was evaporated, compound 3 was purified by means of
HPLC (C-18 column; gradient: from 60% of acetonitrile
in water to 100% of acetonitrile; retention time of 3:
13.6 min).
1
3.2.2. Mixture of (RP,S) and (SP,R) isomers. 31P NMR d
1
(ppm): 38.00; H NMR: d (ppm): 1.27 (t, J = 7.0 Hz, 3H,
CH3 ), 3.93–4.18 (m, 2H, OCH2), 5.10 (d, J = 7.4 Hz,
1H, CHP), 7.20–7.64 (m, 10H, aromatic protons); 13C
NMR d (ppm): 16.69 (d, J = 5.5, CH3), 62.05 (OCH2),
73.79 (d, J = 110.3, CHP), 127.47, 127.50, 128.17, 128.24
(d, J = 2.4), 128.38, 128.47, 132.77, 132.83, 133.12, 136.28
(aromatic carbons).
3.5. Microorganisms: growth and biotransformation
conditions
3.3. Synthesis of ethyl butyryloxy(phenyl)methane-
(P-phenyl)phosphinate 2
The strains of Pseudomonas aeruginosa, Bacillus subtilis,
Serratia liquefaciens and Acinetobacter baumannii were
taken from our own collection. Their taxonomy was previ-
Racemic compound 1 was acylated with butyryl chloride
by the following procedure: 10 mmol of compound 1 was
added to 100 ml of a mixture containing chloroform and
triethylamine (10:1 v/v), followed by the addition of
11 mmol of butyryl chloride. The resulting solution was
stirred for 24 h at room temperature and the product puri-
fied by means of column chromatography as described
above; Rf(2) = 0.73. Ethyl butyryloxy(phenyl)methane(P-
phenyl)phosphinate (1:1 molar ratio) was obtained with
62% yield.
ously analyzed by Deutsche Sammlung fur Mikroorganis-
¨
men und Zellkulturen, Braunschweig, Germany. In order
to achieve the most vigorous growth accompanied by the
best lipolytic activity, several media were tested and the
one of choice is composed of: 10 g of starch soluble, 1 g
of yeast extract, 5 g of (NH4)2SO4, 2 g of K2HPO4, 100 ll
of tributyrin and 1000 ml of distilled water. Microorgan-
isms were incubated for 3 days at 26 ꢁC with shaking at
150 rpm. The cells were then centrifuged at 3000 rpm for
10 min and washed twice in 0.017 M phosphate buffer,
pH 7.0.
3.3.1. Mixture of (RP,R)- and (SP,S)-enantiomers. 31P
NMR d (ppm) 34.93; 1H NMR: d (ppm): 0.87 (t,
J = 7.4 Hz, 3H, CH2CH2CH3), 1.28 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.55–1.62 (m, 2H, CH2CH3), 2.32 (dt,
J = 4.6 Hz, J = 7.4 Hz, 2H, C(O)CH2), 4.00–4.07 (m, 2H,
OCH2), 6.23 (d, J = 8.5 Hz, 1H, CHP), 7.25–7.66 (m,
10H, aromatic protons); 13C NMR d (ppm) 13.71
(CH2CH2CH3), 16.68 (d, J = 5.7 Hz, OCH2CH3), 18.45
(CH2CH2CH3), 36.17 (C(O)CH2), 62.12 (d, J = 6.7 Hz,
OCH2), 72.99 (d, J = 117.3 Hz, CHP), 127.76, 127.78,
Biotransformations were performed in 100 ml of 0.017 M
phosphate buffer, pH 7.0 supplied with 50 ll of substrate.
The samples were shaken at 150 rpm at room temperature.
After the process, biomases were centrifuged, the superna-
tant extracted twice with ethyl acetate and dried over anhy-
drous magnesium sulfate. After filtration, organic solvent
was evaporated and the reaction progress and stereoselec-
tivity analyzed by 31P NMR using quinine as a chiral
discriminator.15

P. Majewska et al. / Tetrahedron: Asymmetry 17 (2006) 2697–2701
2701
3.6. Crystal structure of (RP,S)-hydroxy(phenyl)methane-
(P-phenyl)phosphinate
Acknowledgements
Financial support by the Ministry of Science and Higher
Education 3 T09A 007 28.
X-ray data were collected from a single colorless plate,
0.08 · 0.21 · 0.26 mm, at 100 K using graphite-monochro-
˚
mated CuKa (k = 1.5418 A) radiation on a Xcalibur PX
diffractometer (x- and u-scan). The instrument was
equipped with Oxford Cryosystems low-temperature de-
vices. The data was numerically corrected for absorption
with the use of CRYSALIS RED 1.171, the Xcalibur PX Soft-
ware.16 The structure was solved by direct methods using
the SHELXS-97 program17 and refined by full-matrix least-
squares calculations on F2 with SHELXL-97.18 Non-hydro-
gen atoms were refined with anisotropically thermal
parameters. The H atoms bound to C atoms were included
in geometrically calculated positions, with the C–H dis-
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CCDC 619249 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44)
1223 336033; e-mail: deposit@ccdc.cam.uk).