Resolution of enantiomers of [α-hydroxy-(o-chlorophenyl)methyl] phosphinic acid via diastereomeric salt formation with enantiopure 1-phenylethylamines

Article abstract of DOI:10.1016/j.tetasy.2011.10.019

The resolution of racemic α-hydroxy-H-phosphinic acid with enantiopure 1-phenylethylamines via diastereomeric salt formation was investigated. X-Ray crystallographic analysis of the salt revealed that (R)-1-phenylethylamine to be efficient resolving agent for obtaining a single enantiomer of [α-hydroxy-(o-chlorophenyl)methyl]phosphinic acid. Resolving racemic α-hydroxy-H-phosphinic acid with (S)-2-phenylethylamine also gave access to (S)-α-hydroxyalkylphosphinic acid in good yield.

Full text of DOI:10.1016/j.tetasy.2011.10.019

Tetrahedron: Asymmetry 22 (2011) 1813–1816
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Resolution of enantiomers of [a-hydroxy-(o-chlorophenyl)methyl]phosphinic
acid via diastereomeric salt formation with enantiopure 1-phenylethylamines
Babak Kaboudin a, , Saied Alaie a, Tsutomu Yokomatsu b
⇑
a Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45137-66731, Iran
b School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The resolution of racemic
a-hydroxy-H-phosphinic acid with enantiopure 1-phenylethylamines via
Received 6 October 2011
Accepted 31 October 2011
Available online 17 November 2011
diastereomeric salt formation was investigated. X-Ray crystallographic analysis of the salt revealed that
(R)-1-phenylethylamine to be efficient resolving agent for obtaining a single enantiomer of [ -hydroxy-
(o-chlorophenyl)methyl]phosphinic acid. Resolving racemic -hydroxy-H-phosphinic acid with
(S)-2-phenylethylamine also gave access to (S)- -hydroxyalkylphosphinic acid in good yield.
Ó 2011 Elsevier Ltd. All rights reserved.
a
a
a
1. Introduction
reports in the literature for the separation of chiral
a-hydroxy-H-
phosphinic acids 1 using chiral resolving agents (Scheme 1).
a
-Functionalized phosphinic acids have received considerable
attention in medicinal chemistry and related fields.1–3 Amongst
the -functional phosphinic acids, -hydroxyalkylphosphinic acid
O
O
a
a
R
P
R
P
H
H
derivatives have potential biological activities, such as enzyme
and metalloenzyme inhibitors, bone resorption inhibitors, or as
anti-viral, anti-tumoral and anti-bacterial agents, or fungicides.4–6
OH
OH
OH
OH
(S)-1
(R)-1
Some chiral
for
a-hydroxyphosphinic acids are useful intermediates
-hydroxyphosphinyl peptides showing good inhibitory activity
Scheme 1.
a
against renin.7 In addition, the structure of thephosphinic functional
group mimics the transition state of peptide hydrolysis and the sym-
metric natureof the phosphinicacid derivatives are expected to ben-
efit from their binding to the homodimer of HIV-protease having a
As a part of our ongoing efforts toward the synthesis and sepa-
ration of diastereoisomers of
-functionalized phosphinic acids,13
we have recently described a new method for the synthesis14
and separation of diastereoisomeric and enantiomeric bis(
hydroxyalkyl)phosphinic acids.15 Herein we report the first resolu-
tion of ( )- -hydroxy-H-phosphinic acids 1 via diastereomeric salt
a
a-
C2-axis of symmetry.8 Indeed,
a-hydroxy-H-phosphinic acid deriva-
tives are also used as extractants for the recovery or separation of
a
certain metal ions.9 In contrast to the wide range of literature stud-
formation with enantiopure 1-phenylethylamines.
ied for the separation a
-hydroxyalkylphosphonic acid derivatives,10
very little investigation has been carried out for the chiral separation
2. Results and discussion
of this class of compounds.11 Kielbasinski et al. have reported
the lipase-catalyzed kinetic resolution for
ymethylphosphinate possessing an asymmetric center at the phos-
phorus atom.11a,b The kinetic resolution of
-hydroxy(phenyl)-
phosphinates containing two stereogenic centers at the phosphorus
and the -carbon atom through a lipase-catalyzed acylation has
been reported by Shioji et al.11c Yokomatsu and co-workers have
reported a novel chiral synthesis and separation of -hydroxy-H-
phosphinates with two stereogenic centers via lipase-catalyzed
hydrolysis reactions of the corresponding racemic acetates.11d
Although there is evidence that 1-hydroxy-H-phosphinic acids are
pharmaceutically active,12 to the best our knowledge, there are no
a chiral hydrox-
Racemic ( )-a-hydroxy-H-phosphinic acids 1 were obtained in
multi-gram quantities (45–63% isolated yields, Scheme 2) from the
reaction of an aromatic aldehyde and hypophosphorus acid at reflux
in ethanol for 48 h, according to a literature procedure (Scheme 2).16
In an effort to resolve rac-1, we examined diastereomeric salt forma-
tion with one equivalent of (R)-2-phenylethylamine in a variety of
solvents while expecting one of diastereomeric salts 2 or 3 to be
preferably crystallized (Scheme 3). The 31P NMR spectrum was used
to determine the purity of the separable diastereomeric salts 2 and 3.
The 31P NMR spectrum of the mixtures of crystallized salts of 2a–c
and 3a–c exhibited no resolvable peaks. We were pleased to find
that when rac-1d was treated with (R)-2-phenylethylamine in EtOH
at reflux, the 31P NMR spectra of the mixture of the crystallized salts
2d and 3d exhibited two singlet peaks at 19.04 and 19.11 ppm. Salt
a
a
a
⇑
Corresponding author. Tel.: +98 241 415 3220; fax: +98 241 421 4949.
E-mail address: kaboudin@iasbs.ac.ir (B. Kaboudin).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.10.019

1814
B. Kaboudin et al. / Tetrahedron: Asymmetry 22 (2011) 1813–1816
O
O
EtOH
Ar
P
H
P
H
Ar CHO
+
H
reflux, 48 h
45-63 %
OH
OH
OH
1
1a
1b
o-ClC6H4 (63%)
Ar (isolated yield %): ) Ph (52%), ) p-ClC6H4 (48%),
1c)
1d)
m-BrC6H4 (45%),
Scheme 2.
3d was found to precipitate from ethanol in a 32% yield at ambient
temperature. The 31P NMR spectrum of the crystallized salt 3d
exhibited a singlet at d 19.11 ppm. The diastereomeric purity of salt
3d can be readily assessed by 31P NMR spectroscopy. In this case, salt
3d is produced with >98% purity. The selection of the (R)-hand of rac-
1d with (R)-1-phenylethylamine was confirmed by X-ray crystallog-
raphy (Fig. 1) after recrystallisation. Since it is difficult to precisely
determine the absolute structure by purely crystallographic meth-
ods, the known chirality of the (R)-1-phenylethylamine moiety
was used as an internal reference. Treatment of salt 3d with concd
HCl gave enantiopure (R)-1d in a quantitative yield (Scheme 4). It
should be noted that salt 2d was found to precipitate out of the res-
idue from ethanol in a 33% yield at ambient temperature. The 31P
NMR spectrum of the crystallized salt 2d exhibited a singlet at d
19.04 ppm. Treatment of salt 2d with concd HCl gave enantiopure
(S)-1d in a quantitative yield.
Figure 1. ORTEP drawing (R)-1-phenylethanaminium (R)-[
phenyl)methyl]phosphinate (R,R)-3d.
a-hydroxy-(o-chloro-
salts formed from racemic ( )-a-hydroxy-H-phosphinic acids 1
and enantiopure 1-phenylethylamine. The present resolution
method could open up the possibility to prepare optically active
a-hydroxy-H-phosphinic acid derivatives with biological activity.
4. Experimental
Resolving rac-1d with (S)-1-phenylethylamine in EtOH by the
same procedure as described above, gave access to (S)-1d in a
30% yield (Scheme 4).
4.1. Materials and methods
It is noteworthy that while other solvents, such as methanol and its
mixtures with water were not suitable for obtaining good crystals due
to excessive solubility of the intended salt in the solvents, good crystals
of diastereomeric salts 2d and 3d could be prepared in 2-propanol.
However both the diastereomeric salts 2d and 3d were found to precip-
itate more quickly from ethanol at ambient temperature.
Since 1-phenylethylamine is readily available in both enantio-
meric forms, the resolution procedure above gives access to both
enantiomers of ( )-a-hydroxy-H-phosphinic acids 1.
All chemicals were commercial products and distilled or recrys-
tallized before use. All melting points were obtained by a Buchi 510
and are uncorrected. Optical rotations were recorded on a Perkin-
Elmer 341 with a path length of 0.1 dm using the 589.3 nm D-line
of sodium. Solutions were prepared using spectroscopic grade sol-
vents and concentrations (c) are quoted in g/100 mL. The infrared
(IR) spectra were determined using an FT-IR Brucker-Vector 22.
NMR spectra were taken with a 400 Brucker Avance instrument
with the chemical shifts being reported as d ppm and couplings ex-
pressed in Hertz. Silica gel column chromatography was carried
out with Silica gel 100 (Merck No. 10184).
3. Conclusion
X-Ray crystal data of 3d were collected by a Bruker SMART APEX
II diffractometer. The structure was solved by a direct method using
We have shown that enantiomerically pure a-hydroxy-H-phos-
phinic acids 1 can be accessed via fractional crystallization of the
O
P
O-
O
O
Ph
Me
Ph
Me
Ar
Ar
P
O-
Ar
P
Ph
Me
NH2
C2H5OH
H
H
H
+
+
OH
+
+
NH3
NH3
OH
OH
OH
3
rac-1
2
Scheme 3.
O
P
O-
Ph
Ph
Me
C2H5OH
C2H5OH
HCl
HCl
O
Ph
Ph
Me
(S)-1d
H
NH2
P
+
+
H
NH3
Cl
Cl
OH
OH
Cl
OH
Me
O
P
O-
Me
(R)-1d
rac-1d
NH2
H
+
NH3
OH
3d
Scheme 4.

B. Kaboudin et al. / Tetrahedron: Asymmetry 22 (2011) 1813–1816
1815
SHLEXS-97 (Scheldrik, 1997) and refined with
a
full matrix
4.3. (ꢀ)-(R)-[
a-Hydroxy-(o-chlorophenyl)methyl]phosphinic
laser-squares method. Molecular formula = C15H19NClO3P, MW =
327.73, monoclinic, space group = P21, a = 7.0406(11) Å, b =
23.201(4) Å, c = 9.8854(15) Å, V = 1614.7(4) Å3, T = 90 K, Z = 4,
acid 1d
Racemic [a-hydroxy-(o-chlorophenyl)methyl]phosphinic acid
Dx = 1.348 mg/m3, (Mo-K
a) = 0.71073 Å, R = 0.0426 over indepen-
1d (1.0 g, 5 mmol) and (R)-1-phenylethylamine (0.64 mL, 5 mmol)
were dissolved in refluxing ethanol (15 mL). After refluxing for 5 h
heating was stopped, and the flask was left to gradually cool and
then kept at ambient temperature for 3–4 days. The resulting
white solid was collected by filtration, washed with ethanol
(2 mL in total), and dried in vacuo. The crude product was recrys-
dent reflections. Crystallographic data (excluding structure factors)
for the X-ray crystal structure analysis reported in this paper have
been deposited with the Cambridge Crystallographic Data Center
(CCDC) as supplementary publication No. CCDC 838013, copies of
these data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033
or e-mail: deposit@ccdc.cam.ac.uk].
tallised from ethanol to yield (R)-1-phenylethanaminium (R)-[a-
hydroxy-(o-chlorophenyl)methyl]phosphinate (R,R)-3d in a 32%
yield as a white crystalline solid: mp 158–159 °C (ethanol);
½
a 2D0
ꢁ
¼ ꢀ37:5 (c 0.37, EtOH); 1H NMR (CD3SOCD3-400 MHz): 1.45
4.2. ( )-a-Hydroxy-H-phosphinic acids 1
(3H, d, J = 6.8 Hz), 3.20–3.60 (1H, br, –OH), 3.24 (1H, q,
1
J = 6.8 Hz), 4.79 (1H, d, J = 10.0 Hz), 6.75 (1H, d, JHP = 526 Hz),
7.15–7.55 (9H, m), 8.60–8.80 (3H, br, –NH3); 31P NMR
(CD3SOCD3/H3PO4-162.0 MHz): 19.11; 13C NMR (CD3SOCD3-
100.6 MHz): 21.4, 50.3, 71.0 (d, JPC = 95.0 Hz), 126.9 (d,
JPC = 2.0 Hz), 127.2, 127.8 (d, JPC = 5.0 Hz), 128.6, 128.9, 129.1,
129.2 (d, JPC = 4.0 Hz), 131.9 (d, JPC = 5.0 Hz) 139.9, 140.5. HRMS
calcd for C15H19NClO3P (MH+): 328.0869. Found: 328.0873. The
salt (R,R)-3d (0.26 g, 0.8 mmol) was suspended in ethyl acetate
(50 mL) and 5% aqueous HCl (50 mL) was added. The biphasic mix-
ture was stirred rapidly until all of the solid had dissolved. The or-
ganic layer was separated and the aqueous layer was re-extracted
with ethyl acetate (3 ꢂ 50 mL). The combined organic layers were
washed with water (100 mL), dried over MgSO4, and concentrated
to give (R,R)-1 (0.16 g, quantitative) as a white crystalline solid: mp
This compound was obtained according to a method reported in
the literature.15 The aldehyde (30 mmol) was added to a solution of
hypophosphorus acid (30 mmol-anhydrous) in 100 mL of ethanol
and the resulting solution was stirred for 48 h at reflux. The solvent
was evaporated and chromatography on silica gel with MeOH/
CHCl3 (1:9 to 10/0)) gave the pure product in 48–63% isolated
yields. All products gave satisfactory spectroscopic data in accor-
dance with the assigned structures.
4.2.1. [
White solid: mp 111–112 °C (methanol) [lit. mp 107–108 °C];17
FT IR (KBr)
max: 3371, 3300–2200, 1639, 1191 (P@O), 981; 1H
a-Hydroxy-(phenyl)methyl]phosphinic acid 1a
m
NMR (CD3SOCD3-400 MHz): 4.77 (1H, d, J = 8.8 Hz), 6.76 (1H, d,
1JHP = 529 Hz), 6.10–7.0 (1H, br, OH), 7.20–7.50 (5H, m); 31P NMR
(CD3SOCD3/H3PO4-162.0 MHz): 28.36; 13C NMR (CD3SOCD3-
100.6 MHz): 72.0 (d, JPC = 108 Hz), 127.5 (d, JPC = 6.0 Hz), 127.7 (d,
JPC = 3.0 Hz), 128.3 (d, JPC = 2.0 Hz) 138.1; HRMS calcd for C7H9O3P-
Na (MNa+): 195.0187. Found: 195.0185.
169–170 °C (ethanol); ½a D20
¼ ꢀ32:2 (c 0.87, EtOH). Other spectro-
ꢁ
scopic data were identical to those of rac-1d. FT IR (KBr) mmax
:
3299, 3300–2200, 1163 (P@O), 1027; 1H NMR (CD3SOCD3-
1
400 MHz): 5.16 (1H, d, J = 10.0 Hz), 6.81 (1H, d, JHP = 536 Hz),
6.10–6.8 (1H, br, OH), 7.30–7.60 (4H, m); 31P NMR (CD3SOCD3/
H3PO4-162.0 MHz): 26.83; 13C NMR (CD3SOCD3-100.6 MHz): 68.8
(d, JPC = 109 Hz), 127.6 (d, JPC = 3.0 Hz), 129.4 (d, JPC = 2.0 Hz),
129.5 (d, JPC = 3.0 Hz), 129.7 (d, JPC = 5.0 Hz), 132.2 (d, JPC = 6.0 Hz)
136.3.
4.2.2. [a-Hydroxy-(p-chlorophenyl)methyl]phosphinic acid 1b
White solid: mp 122–123 °C (methanol); FT IR (KBr) mmax: 3285,
3300–2200, 1647, 1158 (P@O), 971; 1H NMR (CD3SOCD3-
1
400 MHz): 4.80 (1H, d, J = 8.8 Hz), 6.77 (1H, d, JHP = 540 Hz),
6.10–7.0 (1H, br, OH), 7.25–7.50 (4H, m); 31P NMR (CD3SOCD3/
H3PO4-162.0 MHz): 27.68; 13C NMR (CD3SOCD3-100.6 MHz): 71.1
(d, JPC = 107 Hz), 128.4 (d, JPC = 2.0 Hz), 129.2 (d, JPC = 5.0 Hz),
132.4, 137.1; HRMS calcd for C7H8O3ClPNa (MNa+): 228.9797.
Found: 228.9800.
4.4. (+)-(S)-[a-Hydroxy-(o-chlorophenyl)methyl]phosphinic
acid 1d
Salt (S,R)-2d was found to precipitate from ethanol in a 33%
yield at ambient temperature via fractional crystallization of the
residue from the separation step of (R,R)-3d (Section 4.3). The
resulting white solid was collected by filtration, washed with eth-
anol (2 mL in total), and dried in vacuo. The crude product was
recrystallised from ethanol to yield (R)-1-phenylethanaminium
4.2.3. [a-Hydroxy-(m-bromophenyl)methyl]phosphinic acid 1c
White solid: mp 100–101 °C (methanol); FT IR (KBr) mmax: 3274,
3300–2200, 1577, 1163 (P@O), 961; 1H NMR (CD3SOCD3-
1
400 MHz): 4.82 (1H, d, J = 9.2 Hz), 6.80 (1H, d, JHP = 536 Hz),
(S)-[a-hydroxy-(o-chlorophenyl)methyl]phosphinate (S,R)-2d in
6.10–7.0 (1H, br, OH), 7.25–7.80 (4H, m); 31P NMR (CD3SOCD3/
H3PO4-162.0 MHz): 27.51; 13C NMR (CD3SOCD3-100.6 MHz): 71.1
(d, JPC = 107 Hz), 121.8 (d, JPC = 3.0 Hz), 126.5 (d, JPC = 5.0 Hz),
130.0 (d, JPC = 5.0 Hz), 130.6 (d, JPC = 2.0 Hz), 140.9; HRMS calcd
for C7H9O3BrP (MH+): 250.9473. Found: 250.9473.
33% yield as a white crystalline solid: mp 156–157 °C (ethanol);
½
a 2D0
ꢁ
¼ þ38:4 (c 0.36, EtOH); 31P NMR (CD3SOCD3/H3PO4-
162.0 MHz): 19.04;). Other spectroscopic data were identical to
those of (R,R)-3d. Following the above procedure (S)-1d obtained
from ent-2d as a white solid in a quantitative yield: ½a D20
¼ þ30:2
ꢁ
(c 0.79, EtOH). Other spectroscopic data were identical to those
of rac-1d.
4.2.4. [a-Hydroxy-(o-chlorophenyl)methyl]phosphinic acid 1d
White solid: mp 169–170 °C (methanol); FT IR (KBr) mmax: 3299,
3300–2200, 1163 (P@O), 1027; 1H NMR (CD3SOCD3-400 MHz):
1
Acknowledgements
5.16 (1H, d, J = 10.0 Hz), 6.81 (1H, d, JHP = 536 Hz), 6.10–6.8 (1H,
br, OH), 7.30–7.60 (4H, m); 31P NMR (CD3SOCD3/H3PO4-
162.0 MHz): 26.83; 13C NMR (CD3SOCD3-100.6 MHz): 68.8 (d,
JPC = 109 Hz), 127.6 (d, JPC = 3.0 Hz), 129.4 (d, JPC = 2.0 Hz), 129.5
(d, JPC = 3.0 Hz), 129.7 (d, JPC = 5.0 Hz), 132.2 (d, JPC = 6.0 Hz)
136.3; HRMS calcd for C7H9O3ClP (MH+): 206.9978. Found:
206.9983.
The authors gratefully acknowledge the support from the Insti-
tute for Advanced Studies in Basic Sciences (IASBS) Research Coun-
cil under grant No. G20109IASBS120. The authors thank Mr.
Haruhiko Fukaya, Tokyo University of Pharmacy and Life Sciences
for his helps carrying out the X-ray crystallographic analysis.

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B. Kaboudin et al. / Tetrahedron: Asymmetry 22 (2011) 1813–1816
9. Telegdi, J.; Shaglouf, M. M.; Shaban, A.; Karman, F. H.; Betroti, I.; Mohai, M.;
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