Preparation of dimethyl (R)- and (S)-2-(2-hydroxyphenyl)-2-hydroxyethylphosphonate derived from salicylaldehyde via resolution using (S)-methoxyphenylacetic acid (MPA)

Article abstract of DOI:10.1016/j.tetasy.2006.12.022

The efficient preparation of both enantiomers of dimethyl δ,β-dihydroxyethylphosphonate 2 has been achieved from salicylaldehyde as a starting material, through the resolution of dimethyl (±)-2-(2-O-benzylphenyl)-2-hydroxyethylphosphonate 4 using (S)-meth

Full text of DOI:10.1016/j.tetasy.2006.12.022

Tetrahedron: Asymmetry 18 (2007) 142–148
Preparation of dimethyl (R)- and (S)-2-(2-hydroxyphenyl)-2-
hydroxyethylphosphonate derived from salicylaldehyde
via resolution using (S)-methoxyphenylacetic acid (MPA)
a
a
b
´
´
´
Haydee Rojas-Cabrera, Mario Fernandez-Zertuche, Oscar Garcıa-Barradas,
b
a,
*
´
˜
Omar Munoz-Muniz and Mario Ordonez
˜
˜
aCentro de Investigaciones Quı´micas, Universidad Auto´noma del Estado de Morelos, Av. Universidad 1001,
62209 Cuernavaca, Mor., Mexico
bUnidad de Servicos de Apoyo en Resolucio´n Analı´tica, Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala s/n,
91190 Xalapa, Ver., Mexico
Received 13 December 2006; accepted 27 December 2006
Available online 30 January 2007
Abstract—The efficient preparation of both enantiomers of dimethyl d,b-dihydroxyethylphosphonate 2 has been achieved from salicyl-
aldehyde as a starting material, through the resolution of dimethyl ( )-2-(2-O-benzylphenyl)-2-hydroxyethylphosphonate 4 using (S)-
methoxyphenylacetic acid (MPA). The absolute configuration was assigned by the Dale and Mosher approach using extended Newman
projections and ab initio calculations.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
yethylphosphonate 4 derived from salicylaldehyde via their
diastereoisomeric esters formed with (S)-methoxyphenyl-
acetic acid (MPA). A diastereoisomeric mixture of (S,S)-5
and (R,S)-6 was easily separated by column chromatogra-
phy and efficiently converted into dimethyl b,d-
dihydroxyethylphosphonate 2. The assignment of the abso-
lute configuration of enantiomerically pure (S,S)-5 and
Phosphonates and their derivatives have attracted consider-
able interest in recent years because of their application as
enzymatic inhibitors, metabolic probes, mimetic peptides,
antibiotics and pharmacological agents,1 in addition to
their traditional application as intermediates in organic syn-
thesis.2 In particular, enantiomerically pure b-hydroxy-
alkylphosphonates of type 1 have received significant atten-
tion due to their potential biological activity and versatility
as substrates for the synthesis of organophosphorus deriva-
tives.3 For these reasons, several synthetic routes for the
preparation of b-hydroxyalkylphosphonates 1 have been
developed, which involve the stereoselective reduction of
the corresponding b-ketophosphonates4 and by biocatalytic
synthesis.5 Recently, we have described two alternative syn-
thesis of c-amino-b-hydroxyphosphonic acids via diastereo-
selective reduction of c-amino-b-ketophosphonates6 and by
resolution of c-amino-b-hydroxyphosphonates using (S)-
methoxyphenylacetic acid (MPA).7 Herein, we report the
resolution of dimethyl 2-(2-O-benzylphenyl)-2-hydrox-
1
(R,S)-6 was made by H NMR based on the Dale and
Mosher approach8 using the extended Newman projections
and ab initio calculations.
O
OH
O
OH
P(OR')2
P(OR')2
R
R
(R
)-1
(S)-1
O
O
OH
OH
OH OH
P(OMe)2
P(OMe)2
(S)-2
(R)-2
2. Results and discussion
*
As shown in Scheme 1, the racemic b-hydroxyphosphonate
4 was obtained in two steps from commercially available
Corresponding author. Tel./fax: +52 777 329 7997; e-mail: palacios@
ciq.uaem.mx
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.022

H. Rojas-Cabrera et al. / Tetrahedron: Asymmetry 18 (2007) 142–148
143
salicylaldehyde. In this context, the reaction of salicylalde-
hyde with excess of benzyl bromide in the presence of
K2CO3 under reflux in acetone afforded the 2-benzyloxy-
benzaldehyde 3 in an 85% yield,9 which by treatment with
the lithium enolate obtained from dimethyl methylphosph-
onate and n-BuLi at À78 ꢁC in THF gave ( )-b-hydroxy-
phosphonate 4 in an 85% yield (Scheme 1).
this context, the reaction of (S)-methoxyphenyl acyl chlo-
ride 7 readily obtained from (S)-methoxyphenylacetic acid
and thionyl chloride, with the 2-hydroxyphosphonate ( )-4
in the presence of triethylamine and catalytic amounts of
DMAP in dry tetrahydrofuran at room temperature affor-
ded mandelates (S,S)-5 and (R,S)-6 in 48% and 41% yields,
respectively, after chromatographic separation (Scheme 3).
O
O
O
OH
P(OMe)2
BnBr/K2CO3
H
H
acetone, Δ
OH
OBn
OBn
85%
3
( )-4
O
MeP(OMe)2
n-BuLi, THF, -78 o
MeO
O
Ph
Cl
85%
Et3N, DMAP
THF, 25 o
C
C
7
O
OH
P(OMe)2
(S,S)-5; 48%
(R,S)-6; 41%
+
OBn
( )-4
Scheme 3.
With the diastereoisomerically pure (S,S)-5 and (R,S)-6 in
hand, the next step was the assignment of the absolute con-
figuration of the stereogenic center at C2. For this purpose,
we initially used the classical approach developed by Dale
and Mosher,8 which is based on the analysis of chemical
shift changes in 1H NMR spectral data in the diastereoiso-
merically pure mandelates. Thus, according to the Trost
model,10 the different orientation of the phenyl ring of
the mandelic moiety on the extended Newman projections
(Fig. 1), could leads to a selective shielding or deshielding
of CH2P(O)(OMe)2 and 2-(O-benzylphenyl) groups around
the asymmetric center, and the spatial relationship between
CH2P(O)(OMe)2/2-(O-benzylphenyl) groups and the phe-
nyl ring of the mandelic acid fragment could be correlated
with the chemical shift changes.11,12 Therefore, it is ex-
pected that the phosphonate group [CH2P(O)(OMe)2] in
the less polar diastereoisomer will be shielded at a higher
field than in the more polar diastereoisomer by the phenyl
ring. The chemical shifts observed in 1H and 31P NMR for
both less and more polar diastereoisomerically pure (S,S)-5
and (R,S)-6 are summarized in Table 1.
Scheme 1.
Having efficiently prepared the racemic b-hydroxyphos-
phonate ( )-4, we turned our attention to its resolution.
Thus, the reaction of dimethyl 2-(2-O-benzylphenyl)-2-
hydroxyethylphosphonate ( )-4 with (S)-methoxyphenyl-
acetic acid (MPA) in the presence of 1,3-dicyclohexylcarbo-
diimide (DCC) and a catalytic amount of 4-(N,N-
dimethylamino)pyridine (DMAP) in dichloromethane at
room temperature, afforded the mixture of diastereoiso-
meric mandelates (S,S)-5 and (R,S)-6, which were sepa-
rated by column chromatography, obtaining (S,S)-5 as
the less polar diastereoisomer and (R,S)-6 as the more
polar diastereoisomer in 45% and 47% yields, respectively
(Scheme 2).
O
OH
P(OMe)2
OBn
( )-4
MeO
Ph
DCC, DMAP
CH2Cl2, 25 o
C
O
O
OMe
OH
O
H
CH2P(OMe)2
H
MeO
Ph
Ph
O
Ph
MeO
O
MeO
O
OBn
Ph
(MeO)2PCH2
H
H
H
BnO
H
d
O
O
O
O
+
P(OMe)2
O
P(OMe)2
(S,S)-5
H
a
c
H
b
OBn
OBn
BnO
OMe
H
(S,S)-5; 45%
(R,S)-6; 47%
O
H
MeO
Ph
H
H
a
O
Scheme 2.
O
H
Ph
CH2P(OMe)2
O
H
H
b
CH2P(OMe)2
H
However, under these conditions several filtration steps
were necessary to completely eliminate the 1,3-dicyclohex-
ylurea (DCU) from the desired mandelates. Therefore, we
decided to use an alternative methodology for the prepara-
tion of diastereoisomerically pure (S,S)-5 and (R,S)-6. In
(R,S)-6
OBn
c
d
Figure 1. Extended Newman projections for the diastereoisomers (S,S)-5
and (R,S)-6.

144
H. Rojas-Cabrera et al. / Tetrahedron: Asymmetry 18 (2007) 142–148
Table 1. 1H and 31P NMR chemical shifts for diastereoisomerically pure (S,S)-5 and (R,S)-6
Entry
Group
More polar mandelate
Less polar mandelate
Dd (ppm)
1
2
3
4
5
CH2
CH2
P(OCH3)
P(OCH3)
(CH3O)2P
2.32
2.41
3.55
3.58
29.56
2.36
2.36
3.36
3.39
29.17
0.04
0.05
0.19
0.19
0.39
O
CH2P(OMe)2
OCH2Ph
6
7
8
9
10
CH2Ph
Ha
Hb
Hc
Hd
5.03
6.85
7.14
6.66
6.66
5.09
6.90
7.22
6.90
7.22
0.06
0.05
0.08
0.24
0.56
Ha
Hd
Hb
Hc
From the NMR data of the diastereoisomerically pure
mandelates summarized in Table 1, we observed that the
1H NMR chemical shifts for the (MeO)2P group in the less
polar diastereoisomer are at a higher field (3.36 and
3.39 ppm) than those for the same group in the more polar
diastereoisomer (3.55 and 3.58 ppm), with Dd = 0.19 ppm
(entries 3 and 4). The 31P NMR chemical shift for the
(MeO)2P group in the less polar diastereoisomer is also
at a higher field (29.17 ppm) than that of the same group
in the more polar diastereoisomer (29.56 ppm) with a
Dd = 0.39 ppm, (entry 5). Additionally, in the more polar
diastereoisomer, the Hc and Hd aromatic protons are at a
higher field (6.66 ppm) than those of the same protons in
the less polar diastereoisomer (6.90 and 7.22 ppm), with a
Dd = 0.24 and 0.56 ppm, respectively. Therefore, these
NMR data show that the less polar mandelate correlates
with the diastereoisomer of configuration (S,S)-5 and the
more polar mandelate with the diastereoisomer (R,S)-6.
shifts for the CH2P(O)(OMe)2 group in the less polar dia-
stereoisomer are at a higher field than those of the same
group in the more polar diastereoisomer, and also the
chemical shifts for the benzylic and aromatic carbons in
the more polar diastereoisomer are at higher field than
those of the same group in the less polar mandelate. These
data again show that the less polar mandelate is the diaste-
reoisomer (S,S)-5, and the more polar mandelate is the
diastereoisomer (R,S)-6.
In addition to the NMR analysis mentioned above, a com-
plexation experiment of the diastereoisomers (S,S)-5 and
(R,S)-6 with barium(II) was accomplished. According to
this protocol, the 1H NMR spectra of each diastereoisomer
were recorded in MeCN-d3 after of the addition of
Ba(ClO4)2.13 The chemical shifts observed in 1H and
31P NMR for both diastereoisomers (S,S)-5 and (R,S)-6
are summarized in Table 3.
In a similar manner, analysis of the more and less polar
mandelates by 13C NMR (Table 2) shows that the chemical
As a result of the complexation with Ba2+, one conformer
is preferentially stabilized as shown in Figure 2. In the fixed
Table 2. 13C NMR chemical shifts for diastereoisomerically pure (S,S)-5 and (R,S)-6
Entry
Group
More polar mandelate
Less polar mandelate
Dd (ppm)
1
2
3
CH2
P(OCH3)
P(OCH3)
31.0
52.46
52.52
30.6
52.16
52.22
0.40
0.30
0.30
O
CH2P(OMe)2
4
5
6
7
8
CH2Ph
Ca
Cb
70.38
111.85
128.10
120.92
125.88
76.38
112.23
128.11
121.10
126.72
0.00
0.38
0.01
0.18
0.84
OCH2Ph
a
Cc
Cd
d
b
c
Table 3. 1H NMR chemical shifts for (S,S)-5/Ba2+ and (R,S)-6/Ba2+ in MeCN-d3
Entry
Group
More polar mandelate Ba2+
Less polar mandelate Ba2+
Dd (ppm)
1
2
3
4
CH2
2.48
3.60
3.66
2.46
3.40
3.41
0.02
0.02
0.25
0.33
O
P(OCH3)
P(OCH3)
(CH3O)2P
CH2P(OMe)2
28.85
28.52
OCH2Ph
5
6
7
8
9
CH2Ph
Ha
Hb
Hc
Hd
5.04
6.95
7.19
6.66
6.66
5.15
6.99
7.31
6.99
7.31
0.11
0.04
0.12
0.33
0.65
Ha
Hd
Hb
Hc

H. Rojas-Cabrera et al. / Tetrahedron: Asymmetry 18 (2007) 142–148
145
Ba2+
plane (Fig. 4a). The protecting effect of the phenyl ring is
now directed toward the aromatic protons of the salicyl-
aldehyde fragment, which is in agreement with the H NMR
data. In a similar manner, it was possible to observe a cor-
relation between the dipole moment in the most stable con-
former for each diastereoisomer and their polarities. Thus,
the more polar mandelate (R,S)-6 shows a dipole moment
of 5.10 Db, whereas the less polar mandelate (S,S)-5 shows
a dipole moment of 2.87 Db. These theoretical results rein-
force the experimental observations.
O
O
O
H
O
H
Ba2+
CH2P(OMe)2
CH2P(OMe)2
1
MeO
Ph
MeO
Ph
O
O
H
H
BnO
BnO
(S,S)-5 + Ba2+
(S,S)-5
Ba2+
BnO
H
BnO
H
O
O
Ba2+
MeO
Ph
MeO
Ph
O
O
CH2P(OMe)2
CH2P(OMe)2
O
H
H
O
(R,S)-6
(R,S)-6 + Ba2+
Figure 2. Complexation of mandelates (S,S)-5 and (R,S)-6 with Ba(II).
conformation, the protecting effect of the phenyl ring from
the MPA fragment is more pronounced than that in the
first set of experiments carried out in the absence of a bar-
ium salt. Hence, the values for Dd have a significant incre-
ment, as shown in Table 3, while the same tendency in the
selective shielding is maintained, as before DdBa = d[(R,S)-
6/Ba2+] À [d(S,S)-5/Ba2+].
Figure 4. Minimum energy conformer for the mandelate (R,S)-6.
Once the absolute configuration was assigned, the prepara-
tion of both enantiomers of dimethyl 2-(2-hydroxyphenyl)-
2-hydroxyethylphosphonate 2 was completed. In this
context, hydrolysis of diastereoisomerically pure (S,S)-6
with LiOH in a mixture of MeOH–H2O (8:2) at room
temperature afforded the enantiomerically pure b-hydr-
oxyethylphosphonate (S)-4 in a 80% yield. Cleavage of
the benzyl group in (S)-4 using Pd/C as a catalyst in meth-
anol under a hydrogen atmosphere at room temperature
gave the dimethyl (S)-2-(2-hydroxyphenyl)-2-hydroxy-
ethylphosphonate (S)-2 in a 90% yield. In a similar way,
enantiomer (R)-2 was obtained from (R,S)-6 (Scheme 4).
In addition to the NMR experiments, computational calcu-
lations were carried out in order to find the most stable
conformer for each diastereoisomeric mandelate.14 Confor-
mational search and geometry optimization were made
using ab initio calculations, and a global minimum was
obtained. The employed method was Hartree–Fock with
the basis set 6-311 + G**.
Results from this conformational analysis showed that the
most stable conformer for the diastereoisomer (S,S)-5 has
the geometry predicted by Mosher’s approximation, that
is with the methoxy and carbonyl groups of MPA and
the proton b to the phosphorus atom lying on the same
plane (Fig. 3a). The phenyl ring is oriented to the same side
of the (MeO)2P group. In addition to this protection effect,
there is an extra shielding by the aromatic ring of the ben-
zyl moiety (Fig. 3b).
Ph
O
MeO
O
Ph
O
MeO
O
O
O
P(OMe)2
P(OMe)2
OBn
OBn
(
R,S
)-6
(S,
S
)-5
LiOH
MeOH:H2O
LiOH
MeOH:H2O
80%
80%
O
O
OH
OH
P(OMe)2
P(OMe)2
Figure 3. Minimum energy conformer for the mandelate (S,S)-5. Some 1H
atoms were omitted for clarity.
OBn
)-4
OBn
(
S
(
R)-4
H2
H2
90%
90%
Pd/C
Pd/C
On the other hand, the conformational search for the dia-
stereoisomer (R,S)-6 exhibited a molecular geometry in
which the methoxy and carbonyl groups of MPA and the
proton b to the phosphorus atom are almost on the same
(R)-2
(S)-2
Scheme 4.

146
H. Rojas-Cabrera et al. / Tetrahedron: Asymmetry 18 (2007) 142–148
3. Conclusion
obtaining (S,S)-5 (1.30 g, 45%) (less polar) and (R,S)-6
(1.35 g, 47%) (more polar) both as yellow oils.
In conclusion, we have found a methodology for the
preparation of enantiomerically pure dimethyl (R)- and
Procedure B: To a solution of ( )-4 (1.15 g, 3.42 mmol)
and 4-(N,N-dimethyl)aminopyridine (0.125 g, 1.026 mmol)
in dry THF were added (S)-methoxyphenylacetic acid chlo-
ride (1.14 g, 6.154 mmol) and triethylamine (0.62 g,
0.86 mL, 6.15 mmol) at room temperature. After 10 h the
solvent was evaporated under reduced pressure and the res-
idue was purified by column chromatography (ethyl ace-
tate–hexane 8:2) obtaining (S,S)-5 (0.80 g, 48%) (less
polar) and (R,S)-6 (0.68 g, 41%) (more polar) both as yel-
low oils.
(S)-2-(2-hydroxyphenyl)-2-hydroxyethylphosphonates
2
from salicylaldehyde, which are versatile intermediates in
organic chemistry. As a matter of fact, we are already using
these hydroxyphosphonates as catalyst for the addition of
cyanide to aldehydes.
4. Experimental
Optical rotations were taken on a Perkin–Elmer 241 polar-
imeter in a 1 dm tube; concentrations are given in
g/100 mL. For flash chromatography, silica gel 60 (230–
400 mesh ASTM) was used. 1H NMR (400 MHz) and
13C NMR (100 MHz) spectra were registered on a Varian
INOVA 400, and 31P NMR (80.98 MHz) on a Varian Mer-
cury 200. The spectra were recorded in CDCl3 solution
using TMS as internal reference. HRMS spectra were
recorded on a JEOL JMS-700. Flasks, stirring bars and
hypodermic needles used for the generation of organo-
metallic compounds were dried for ca. 12 h at 120 ꢁC and
allowed to cool in a desiccator over anhydrous calcium
sulfate. Anhydrous solvents (ethers) were obtained by dis-
tillation from benzophenone ketyl. The 2-(benzyloxy)-
benzaldehyde 3 was prepared according to literature
procedure.9
4.2.1. Dimethyl (S)-2-(2-O-benzylphenyl)-2-[(S)-O-methyl-
mandelate]ethylphosphonate (S,S)-5. [a]D = +26.89 (c
1.8, CHCl3). 1H NMR (400 MHz, CDCl3): d 2.36 (dd,
J = 17.6, 6.4 Hz, 2H, CH2P), 3.36 (d, J = 10.8 Hz, 3H,
(CH3O)2P), 3.39 (d, J = 10.8 Hz, 3H, (CH3O)2P), 3.39 (s,
3H, CH3OCH), 4.81 (s, 1H, CHOCH3), 5.09 (s, 2H,
CH2Ph), 6.44 (dt, JH/P = 11.2, J = 6.4 Hz, 1H, CHCH2P),
6.90 (d, J = 8.0 Hz, 2H, Ha and Hc), 7.22 (d, J = 8.0 Hz,
2H, Hb and Hd), 7.29–7.48 (m, 10H, Harom). 13C NMR
(100 MHz, CDCl3): d 30.6 (d, J = 138.2 Hz, CH2P), 52.1
(d, J = 6.1 Hz, (CH3O)2P), 52.2 (d, J = 6.1 Hz, (CH3O)2P),
57.6 (CH3OCH), 67.6 (d, J = 3.1 Hz, CHCH2P), 70.4
(OCH2Ph), 82.9 (CHOCH3), 112.2, 121.1, 126.7, 127.4,
127.5, 127.6, 127.6, 128.1, 128.2, 128.4, 128.6, 128.7,
128.8, 128.9, 129.5, 136.1, 136.8, 155.3, 169.6 (CO). 31P
NMR (80.98 MHz, CDCl3): d 29.17. HRMS, (CI+,
CH4) calcd for C26H30O7P (MH+) 485.1724, found 485.1704.
4.1. Dimethyl ( )-2-(2-O-benzylphenyl)-2-hydroxyethylphos-
phonate ( )-4
4.2.2. Dimethyl (R)-2-(2-O-benzylphenyl)-2-[(S)-O-methyl-
mandelate]ethylphosphonate (R,S)-6. [a]D = +27.18 (c
1
A
solution of dimethyl methylphosphonate (1.75 g,
1.7, CHCl3). H NMR (400 MHz, CDCl3): d 2.32 (ddd,
14.1 mmol) and dry THF (70 mL) was cooled at À78 ꢁC
before the slow addition of n-BuLi (6.08 mL, 14.6 mmol)
in hexanes (2.4 M). The resulting solution was stirred at
À78 ꢁC for 1 h, and after this period of time, the solution
was slowly added to another solution of 2-(benzyl-
oxy)benzaldehyde 3 (1.0 g, 4.7 mmol) in THF (60 mL).
The reaction mixture was stirred at À78 ꢁC for 4 h before
the addition of a saturated aqueous solution of NH4Cl.
The organic layer was separated and the aqueous layer
was extracted with ethyl acetate (3 · 60 mL). The com-
bined organic extracts were dried over Na2SO4 and concen-
trated in vacuum. The crude product was purified by
column chromatography (ethyl acetate–hexane 3:1) obtain-
ing ( )-4 (1.4 g, 85%) as a yellow oil. The NMR data are
identical to enantiomerically pure (R)- and (S)-4.
J = 15.6, 15.6, 9.4 Hz, 1H, CH2P), 2.41 (ddd, J = 19.2,
15.6, 3.6 Hz, 1H, CH2P), 3.44 (s, 3H, CH3OCH), 3.55 (d,
J = 11.2 Hz, 3H, (CH3O)2P), 3.58 (d, J = 11.2 Hz, 3H,
(CH3O)2P), 4.87 (s, 1H, CH(OCH3)), 5.03 (s, 2H, CH2Ph),
6.50 (ddd, JH/P = 11.1, J1/3 = 9.5, J1/3 = 3.7 Hz, 1H,
CHCH2P), 6.66 (m, 2H, Hc and Hd), 6.85 (d, J = 8.0 Hz,
1H, Ha), 7.14 (ddd, J = 8.4, 6.0, 3.2 Hz, 1H, Hb), 7.31–
7.45 (m, 10H, Harom). 13C NMR (100 MHz, CDCl3): d
31.0 (d, J = 36.6 Hz, CH2P), 52.4 (d, J = 6.1 Hz,
(CH3O)2P), 52.5 (d, J = 6.1 Hz, (CH3O)2P), 57.7
(CH3OCH), 66.8 (d, J = 4.6 Hz, CHCH2P), 70.4
(OCH2Ph), 82.6 (CHOCH3), 111.8, 120.9, 125.9, 127.5,
127.5, 127.7, 127.7, 128.1, 128.2, 128.3, 128.6, 128.7,
128.8, 128.8, 129.2, 136.2, 136.7, 154.9, 169.2 (CO). 31P
NMR (80.98 MHz, CDCl3): d 29.56. HRMS, (FAB+) calcd
for C26H30O7P (MH+) 485.1724, found 485.1636.
4.2. Mandelates (S,S)-5 and (R,S)-6
4.3. Dimethyl (S)-2-(2-O-benzylphenyl)-2-hydroxyethylphos-
phonate (S)-4
Procedure A: To a mixture of ( )-4 (2.0 g, 5.95 mmol) and
(S)-O-methylmandelic acid (1.58 g, 9.5 mmol) in dry
dichloromethane (100 mL), were added 4-(N,N-dimethyl)-
aminopyridine (110 mg, 0.9 mmol) and 1,3-dicyclohexyl-
carbodiimide (1.96 g, 9.5 mmol). The reaction mixture
was stirred at room temperature for 12 h. After this time,
the 1,3-dicyclohexylurea was filtered off and the filtrate
was concentrated in vacuum. The crude product was puri-
fied by column chromatography (ethyl acetate–hexane 8:2)
Diastereoisomer (S,S)-5 (1.0 g, 2.06 mmol) was dissolved in
a 8:2 mixture of MeOH/H2O (50 mL) and stirred at room
temperature with LiOH (433 mg, 10.3 mmol). After 6 h the
volatiles were removed under reduced pressure. The residue
was washed with a 5% solution of HCl and extracted with
ethyl acetate. The organic layer was dried over Na2SO4 and
concentrated in vacuum. The crude product was purified

H. Rojas-Cabrera et al. / Tetrahedron: Asymmetry 18 (2007) 142–148
147
by column chromatography (ethyl acetate–hexane 8:2) to
give (S)-4 (560 mg, 80%) as a white solid, mp 63 ꢁC.
[a]D = +46.8 (c 1.23, CHCl3). 1H NMR (400 MHz,
CDCl3): d 2.14 (ddd, J = 15.3, 14.8, 9.7 Hz, 1H, CH2P),
2.38 (ddd, J = 18.1, 15.3, 2.7 Hz, 1H, CH2P), 3.58 (d,
J = 10.8 Hz, 3H, (CH3O)2P), 3.59 (d, J = 10.8 Hz, 3H,
(CH3O)2P), 5.02 (d, J = 11.6 Hz, 1H, CH2Ph), 5.08 (d,
J = 12 Hz, 1H, CH2Ph), 5.40 (ddd, J = 12.2, 9.8, 2.6 Hz,
1H, CHAr), 6.92 (d, J = 8.4 Hz, 1H, Harom), 7.00 (ddd,
J = 7.6, 7.2, 0.8 Hz, 1H, Harom), 7.23 (ddd, J = 8.4, 7.4,
1.4 Hz, 1H, Harom), 7.29–7.42 (m, 5H, Harom), 7.56 (dd,
J = 7.4, 1.4 Hz, 1H, Harom). 13C NMR (100 MHz, CDCl3):
d 33.1 (d, J = 133.6 Hz, CH2P), 52.4 (d, J = 6.0 Hz,
(CH3O)2P), 52.5 (d, J = 6.0 Hz, (CH3O)2P), 64.4 (d,
J = 4.5 Hz, CHOH), 70.0 (s, CH2Ph), 111.3, 121.2, 126.2,
127.4, 127.5, 128.1, 128.5, 128.6, 131.8, 131.9, 136.7,
154.6. 31P NMR (80.98 MHz, CDCl3): d 33.39. HRMS,
(CI+, CH4) calcd for C17H22O5P (MH+) 337.1205, found
337.1199.
lowship by H.R.C. (170296). We also thank to Victoria
Labastida for her valuable technical help in carrying out
all MS spectra and elemental analyses.
References
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3. (a) Wroblesky, A. E.; Halajewska-Wosik, A. Tetrahedron:
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4.4. Dimethyl (R)-2-(2-O-benzylphenyl)-2-hydroxyethylphos-
phonate (R)-4
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The procedure is the same as for (S)-4, using the diastereo-
isomer (R,S)-6 as starting material. [a]D = À47.2 (c 1.18,
CHCl3). The NMR data are identical to (S)-4.
`
5. (a) Pamies, O.; Ba¨ckball, J. E. J. Org. Chem. 2003, 68, 4815–
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4.5. Dimethyl (S)-2-(2-hydroxyphenyl)-2-hydroxyethylphos-
phonate (S)-2
Dimethyl (S)-2-(2-O-benzylphenyl)-2-hydroxyethylphos-
phonate (S)-4 (550 mg, 1.6 mmol) was treated with
110 mg (10 wt %) of palladium on carbon in methanol
(20 mL) and stirred for 24 h under a hydrogen atmosphere
at room temperature. The mixture was filtered through a
bed of Celite, and the solvent was concentrated in vacuum.
The crude product was purified by column chromatogra-
phy (ethyl acetate–hexane 5:5) to obtain the enantiomer
(S)-2 (340 mg, 84%), as a colorless oil. [a]D = À0.3 (c 3.0,
CHCl3). 1H NMR (300 MHz, CDCl3): d 2.17 (ddd,
J = 17.4, 8.0 Hz, 2H, CH2P), 2.90 (ddd, J = 12.0, 8.0 Hz,
2H, CHAr), 2.9 (s, 1H, HOCH), 3.69 (d, J = 10.8 Hz,
6H, (CH3O)2P), 6.74–7.10 (4H, Harom), 8.21 (s, 1H,
´
´
6. (a) De la Cruz-Cordero, R.; Labastida-Galvan, V.; Fernan-
´
dez-Zertuche, M.; Ordonez, M. J. Mex. Chem. Soc. 2005, 49,
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Fernandez-Zertuche, M.; Munoz-Hernandez, M. A.; Ordo-
nez, M. Arkivoc 2005, 277–286; (c) Ordonez, M.; De la Cruz-
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´
´
˜
´
´
´
˜
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Cordero, R.; Fernandez-Zertuche, M.; Munoz-Hernandez,
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M. A.; Garcıa-Barradas, O. Tetrahedron: Asymmetry 2004,
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Salazar-Fernandez, H. Tetrahedron: Asymmetry 2004, 15,
2719–2725; (e) Ordonez, M.; De la Cruz-Cordero, R.;
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dez-Zertuche, M.; Munoz-Hernandez, M. A. Tetrahedron:
´
´
˜
´
´
˜
´
´
˜
´
´
˜
´
˜
Asymmetry 2002, 13, 559–562.
HOAr). 13C NMR (50 MHz, CDCl3):
d 24.0 (d,
´
´
´
7. (a) Gonzalez-Morales, A.; Fernandez-Zertuche, M.; Ordo-
nez, M. Rev. Soc. Quı´m. Mex. 2004, 48, 236–242; (b)
Gonzalez-Morales, A.; Dıaz-Coutino, D.; Fernandez-Zertu-
che, M.; Garcıa-Barradas, O.; Ordonez, M. Tetrahedron:
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˜
J = 4.15 Hz, CHOH), 24.9 (d, J = 136.0 Hz, CH2P),
52.8 (d, J = 6.45 Hz, (CH3O)2P), 116.1, 119.9, 127.1,
127.4, 127.8, 129.8, 154.7. 31P NMR (80.98 MHz, CDCl3):
d 37.0. HRMS, (FAB+) calcd for C10H16O5P (MH+)
247.0735, found 247.0000.
´
´
´
˜
´
´
˜
´
´
˜
´
´
1775–1779.
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S.; Varga, S. L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370–
2374.
The procedure is the same as for (S)-2, using (R)-4 as a
starting material. [a]D = +0.3 (c 0.9, CHCl3). The NMR
data are identical to (S)-2.
Acknowledgments
11. For the assignment of absolute configuration of secondary
We gratefully acknowledge to CONACYT-Mexico for the
financial support via Grant 41657-Q and the graduate fel-
´
alcohols by NMR, see: (a) Seco, J. M.; Quinoa, E.; Riguera,
˜
R. Chem. Rev. 2004, 104, 17–117, and references cited therein;

148
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´
Godejohann, M.; Quinoa, E.; Riguera, R. Tetrahedron:
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´
Asymmetry 2002, 13, 2149–2153; (d) Seco, J. M.; Quinoa,
˜
´
´
´
E.; Riguera, R. Tetrahedron: Asymmetry 2001, 12, 2915–2925;
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14. For the assignment of absolute configuration of secondary
alcohols using molecular mechanics and NMR data, see:
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hydroxyphosphonates by NMR, see: Refs. 4–6; (b) Maly, A.;
Lejczak, B.; Kafarski, P. Tetrahedron: Asymmetry 2003, 14,
´
Latypov, S. K.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Org.
Chem. 1996, 61, 8569–8577.
˜