First resolution of (R,R)- and (S,S)-bis(1-hydroxyphenylmethyl)phosphinic acids via diastereomeric salt formation with enantiopure 1-phenylethylamines

Article abstract of DOI:10.1016/j.tetasy.2008.03.004

The resolution of racemic bis(1-hydroxyphenylmethyl)phosphinic acid with enantiopure 1-phenylethylamines via diastereomeric salt formation was investigated. X-ray crystallographic analysis of the salt clearly revealed that (S)-1-phenylethylamine was an ef

Full text of DOI:10.1016/j.tetasy.2008.03.004

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 862–866
First resolution of (R,R)- and (S,S)-
bis(1-hydroxyphenylmethyl)phosphinic acids via diastereomeric
salt formation with enantiopure 1-phenylethylamines
Babak Kaboudin,a,* Hamideh Haghighata and Tsutomu Yokomatsub
aDepartment of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-1159, Iran
bSchool of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 13 February 2008; accepted 6 March 2008
Available online 28 March 2008
Abstract—The resolution of racemic bis(1-hydroxyphenylmethyl)phosphinic acid with enantiopure 1-phenylethylamines via diastereo-
meric salt formation was investigated. X-ray crystallographic analysis of the salt clearly revealed that (S)-1-phenylethylamine was an
efficient resolving agent for obtaining the single enantiomer (R,R)-bis(1-hydroxyphenylmethyl)phosphinic acid. Resolving racemic
bis(1-hydroxyphenylmethyl)phosphinic acid with (R)-2-phenylethylamine gave access to (S,S)-bis(1-hydroxyphenylmethyl)phosphinic
acid in good yield.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
there is evidence that bis(a-hydroxyalkyl)phosphinic acids
are pharmaceutically active.13 As part of our efforts for
the synthesis of organophosphorus compounds,16 we have
recently described a new method for the synthesis17 and
separation of diastereoisomeric bis(a-hydroxyalkyl)phos-
phinic acids18 from the reactions of hypophosphorous acid
with aldehydes. Herein, we report the first resolution of
a-Functionalized phosphinic acid derivatives have
attracted significant attention due to their usefulness both
in medicinal chemistry and materials chemistry.1–7 Among
the a-functional phosphinic acids, a-hydroxyphosphinic
acids are chiral organic molecules involved in a wide
variety of biological processes.8–10 Some chiral a-hydroxy-
phosphinic acids are useful intermediates for a-hydroxy-
phosphinyl peptides showing good inhibitory activity
against renin.11 Symmetric or pseudo-symmetric chiral
bis(a-hydroxyalkyl)phosphinic acid derivatives have also
attracted attention in the design of HIV protease inhibi-
tors.12 In addition, the structure of the phosphinic func-
tional group mimics the transition state of peptide
hydrolysis, while the symmetric nature of the phosphinic
acid derivatives is expected to help in their binding to the
homodimer of HIV-protease with a C2-axis of symmetry.13
Moreover, a-hydroxyphosphinic acid derivatives are useful
intermediates in the synthesis of other phosphorus chiral
organic compounds of material interest.14 In contrast to
the widely studied separation of 1-hydroxyalkylphosphonic
acid derivatives,15 there is no report for the resolution
bis(a-hydroxyalkyl)phosphinic acid derivatives, although
( )-bis(1-hydroxyphenylmethyl)phosphinic acid
1
via
diastereomeric salt formation with enantiopure 1-phenyl-
ethylamines.
O
P
O
P
Ph
Ph Ph
Ph
OH
OH
OH OH
OH OH
(R,R) 1
(S,S) 1
2. Results and discussion
A diastereomeric mixture of bis(a-hydroxyphenylmeth-
yl)phosphinic acid derivatives rac-1 and 2 was obtained
in multi-gram quantities (82% yield in a 56:45 ratio of
diastereoisomers, Scheme 1) by microwave-assisted reac-
tion or by heating with benzaldehyde and hypophosphorus
acid as previously described (Scheme 1).19 It has previously
*
Corresponding author. Tel.: +98 241 415 3220; fax: +98 241 421 4949;
e-mail: kaboudin@iasbs.ac.ir
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.004

B. Kaboudin et al. / Tetrahedron: Asymmetry 19 (2008) 862–866
863
OH
Ph
O
O
P
Ph
P
Ph
HCl (5%)
MeOH/2 h
O
Ph
Ph
O
OH
H
OH
OH
O
H
H
90 ºC/3 h
2
meso-1
H
P
H
Ph CHO
+
O
2
+ 5
OH
Ph
P
Ph
OH
OH
OH
rac-1
Scheme 1.
been noted that when the reaction mixture was subjected to
washing with successively non-polar and polar solvents,
relatively non-polar phosphinic acid 2 was extracted with
chloroform and only rac-1 was extracted with methanol.
Compound 2 was readily converted to phosphinic acid
meso-1 of meso-stereochemistry. The stereochemistry of
rac-1 was confirmed after the conversion to the corre-
sponding methyl ester using trimethyl orthoformate.18
The methyl ester of rac-1 was produced as a single diaste-
reomer. However, under the same conditions, meso-1 was
converted to the corresponding methyl ester as a mixture
of two diastereoisomers, due to the new stereogenic centre
formed.18
In an effort to resolve rac-1, we examined the diastereo-
meric salt formation with 1 equiv of (S)-2-phenylethyl-
amine in a variety of solvents, expecting that one of
diastereomeric salts 3a and 3b would be preferably crystal-
O
Ph
Me
Ph
P
Ph
O
O-
+
NH3
OH
OH
OH
HCl
Ph
P
Ph Ph
+
Me
C2H5OH
(R,R)-1
3a
OH
O
P
OH
OH
NH2
Ph
Ph Ph
Me
rac-1
O-
+
OH
NH3
3b
Scheme 2.
Figure 1. ORTEP drawing of 3a.

864
B. Kaboudin et al. / Tetrahedron: Asymmetry 19 (2008) 862–866
O
O
Ph
Me
NH2
Ph
P
Ph
HCl
Ph
P
Ph Ph
Me
(S,S)-1
+
OH
O-
+
OH
OH
OH OH
NH3
rac-1
ent-3a
Scheme 3.
lized (Scheme 2). We were pleased to find that when rac-1
was treated with (S)-2-phenylethylamine in EtOH at
30–33 °C, only diastereomeric salt 3a was preferably crys-
tallized. Salt 3a was found to precipitate from ethanol in
24% yield at 30–33 °C. The 31P NMR spectrum of crystal-
lized salt 3a exhibited a singlet at d 27.51 ppm, while that of
oily residue composed with salts 3a and 3b showed two
singlets at 27.51 ppm and 27.42 ppm, respectively (Scheme
2). The 1H NMR spectrum exhibited two doublets at d 4.75
and 4.74 ppm indicative of CH–P coupling (JHP = 9.2 Hz
for 3a and 8.0 Hz for 3b). The diastereomeric purity of salt
3a can be readily assessed by a combination with 31P NMR
possibility to prepare optically active bis(1-hydroxyaryl-
methyl)phosphinic acid derivatives with biological activity.
4. Experimental
4.1. Materials and methods
All chemicals were commercial products and distilled or
recrystallized before use. All melting points obtained by a
Buchi 510 and are uncorrected. Optical rotations were
recorded on a CETI Polaris polarimeter with a path length
1 dm using the 589.3 nm D-line of sodium. Solutions were
prepared using spectroscopic grade solvents and concentra-
tions (c) are quoted in g/100 mL. The infrared (IR) spectra
were determined using a FT-IR Brucker-Vector 22. NMR
spectra were taken with a 250 and 500 Brucker Avance
instrument with the chemical shifts being reported as d
ppm and couplings expressed in Hertz. Silica gel column
chromatography was carried out with Silica Gel 100
(Merck No. 10184).
1
and H NMR spectroscopy. In this case, salt 3a is pro-
duced in >98% purity. The selection of the (R,R)-hand of
rac-1 with (S)-1-phenylethylamine was confirmed by X-
ray crystallography (Fig. 1) after recrystallization. Since
it is difficult to determine precisely the absolute structure
by purely crystallographic methods, the known chirality
of the (S)-1-phenylethylamine moiety was used as an inter-
nal reference. The treatment of salt 3a with concd HCl gave
enantiopure (R,R)-1 in quantitative yield (Scheme 2).
Resolving rac-1 with (R)-1-phenylethylamine by the same
procedure descried above as in EtOH gave access to
(S,S)-1 in 21.6% yield (Scheme 3).
X-ray crystal data of 3a were collected by a Bruker
SMART APEX II diffractometer. The structure was solved
by a direct method using SHLEXS-97 (Scheldrik, 1997) and
refined with a full matrix laser-squares method. Molecular
formula = C22H26NO4P, MW = 399.41, orthorhombic,
It is noteworthy that while other solvents, such as methanol
and its mixtures with water, were not suitable for obtaining
good crystals due to the excessive solubility of the intended
salt in the solvents, diastereomeric salts 3a prepared in
2-propanol are good crystals to be isolated in higher yield
(35.3%). Using 2-propanol as a solvent, we were able to
efficiently resolve rac-1 with (R)-1-phenylethylamine and
(S)-1-phenylethylamine to give (S,S)-1 and (R,R)-1 in
35.3% and 31.4% yield, respectively.
˚
space group = P212121, a = 6.4432(19) A, b = 11.049(3)
3
˚
˚
˚
A, c = 28.968(8) A, V = 2062.3(11) A , T = 90 K, Z = 4,
Dx = 1.286 Mg/m3, (Mo-Ka) = 0.71073 A, R = 0.0401
˚
over independent 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 675456, 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].
Since 1-phenylethylamine is readily available in both enan-
tiomeric forms, the resolution procedure above therefore
gives access to both enantiomers of bis(1-hydroxyphenyl-
methyl)phosphinic acid 1.
4.2. (+)-(R)-Hydroxy(phenyl)methyl[(R)-hydroxy(phenyl)-
methyl]phosphinic acid (R,R)-1
3. Conclusion
Racemic bis(1-hydroxyphenylmethyl)phosphinic acid 1
(1.0 g, 3.6 mmol) and (S)-1-phenylethylamine (0.46 mL,
3.6 mmol) were dissolved in refluxing ethanol (24 mL).
After refluxing for 1 h, heating was stopped, and the flask
was left to gradually cool and kept for 6 h at 30–33 °C (cor-
responding to crystallization temperature). The resulting
white solid was collected by filtration, washed with ethanol
(2 mL in total) and dried in vacuo. The materials were
recrystallized from ethanol to yield (S)-1-phenylethan-
We have shown that enantiomerically pure bis(1-hydroxy-
phenylmethyl)phosphinic acid can be accessed by the
fractional crystallization of salts formed from racemic
bis(1-hydroxyphenylmethyl)phosphinic acid and enantio-
pure 1-phenylethylamine. Since we have developed a
method for obtaining a series of racemic bis(1-hydroxy-
arylmethyl)phosphinic acid derivatives,19 a combination
with the present resolution method would open up the

B. Kaboudin et al. / Tetrahedron: Asymmetry 19 (2008) 862–866
865
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aminium (R)-hydroxy(phenyl)methyl[(R) hydroxy(phenyl)-
methyl]phosphinate 3a in 24% yield as a white crystalline
20
solid: mp 212–214 °C (ethanol); ½aꢀD ¼ þ47:2 (c 2.50,
CH3OH); FT-IR (KBr) mmax: 3347, 3300–2200, 1621,
1150 (P@O), 1018; 1H NMR (CD3SOCD3/TMS-500
MHz): 1.27 (3H, d, J = 6.6 Hz), 3.20–3.60 (1H, br, –OH),
3.84 (1H, q, J = 6.4 Hz), 4.74 (2H, d, J = 9.2 Hz), 5.10–
5.30 (1H, br, OH), 7.1–7.45 (15H, m); 31P NMR
(CD3SOCD3/H3PO4—202.4 MHz): 27.77; 13C NMR
(CD3SOCD3/TMS—125.8 MHz): 22.1, 50.7, 68.8 (d,
JPC = 97.4 Hz), 126.4, 127.5, 127.9, 128.0 (d, JPC
=
3.4 Hz), 128.7, 129.3, 141.5, 142.6. Anal. Calcd for
C22H26NO4P: C, 66.1; H, 6.6; N, 3.5. Found: C, 65.9; H,
6.8; N, 3.3. Salt 3a (0.4 g, 1 mmol) was suspended in ethyl
acetate (100 mL) and 5% aqueous HCl (100 mL) was
added. The biphasic mixture was stirred rapidly until all
the solid had dissolved. The organic layer was separated
and the aqueous layer was re-extracted with ethyl acetate
(100 mL). The combined organic layers were washed with
water (100 mL), dried over MgSO4 and concentrated to
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give (R,R)-1 (0.26 g, quantitative) as a white crystalline so-
20
lid: mp 201–203 °C (ethanol); ½aꢀD ¼ þ62:5 (c 1.80,
CH3OH). Other spectral data are identical to those of
rac-1. 1H NMR (CD3SOCD3/TMS—250 MHz): 5.14
(2H, d, J = 7.4 Hz), 4.93 (2H, br, OH), 5.99 (1H, br,
OH), 7.2–7.45 (10H, m); 31P NMR (CD3SOCD3/H3PO4):
38.74; 13C NMR (CD3SOCD3/TMS—62.9 MHz): 68.8 (d,
JPC = 106.7 Hz), 127.3, 127.9, 128.0, 138.9 (d, JPC
=
2.5 Hz). Anal. Calcd for C14H15O4P. C, 60.4; H, 5.4.
Found: C, 60.3; H, 5.3.
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4.3. (ꢁ)-(S)-Hydroxy(phenyl)methyl[(S)-hydroxy(phenyl)-
methyl]phosphinic acid (S,S)-1
Following the above procedure resolving ( )-bis(1-hydr-
oxyphenylmethyl)phosphinic acid rac-1 with (R)-1-phenyl-
ethylamine, gave access to (R)-1-phenylethanaminium
(S)-hydroxy (phenyl)methyl[(S)-hydroxy(phenyl)methyl]-
phosphinate ent-3a in 21.6% yield as a white crystalline
solid. Following the above procedure, (S,S)-1 was obtained
from ent-3a as a white solid in quantitatively yield:
20
½aꢀD ¼ ꢁ62:5 (c 1.80, CH3OH). Other spectral data are
identical to those of rac-1.
Acknowledgements
The Institute for Advanced Studies in Basic Sciences (IAS-
BS) is thanked for supporting this work. The authors thank
Mr. Haruhiko Fukaya, Tokyo University of Pharmacy and
Life Sciences for his help in carrying out the X-ray crystal-
lographic analysis.
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