Convenient synthesis of optically active α-hydroxyphosphinic acids

Article abstract of DOI:10.1002/hc.10150

The reaction of O-menthyl phenylphosphonite 1 with aromatic aldehydes in the presence of Me₃SiCl provided the O-menthyl α-hydroxy-phosphinates 2. Acidic hydrolysis of 2 gave the corresponding α-hydroxyphosphinic acids 3. The (+)-enantiomer of 3

Full text of DOI:10.1002/hc.10150

Heteroatom Chemistry
Volume 14, Number 4, 2003
Convenient Synthesis of Optically Active
α-Hydroxyphosphinic Acids
Juexiao Cai, Zhenghong Zhou, Guofeng Zhao, and Chuchi Tang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China
Received 26 November 2002; accepted 25 December 2002
The reaction is very sluggish without a catalyst.
ABSTRACT: The reaction of O-menthyl phenylphos-
The absolute configuration of the ꢀ-carbon of ꢀ-
phonite 1 with aromatic aldehydes in the pres-
hydroxyphosphonic acid derivatives has an impor-
ence of Me3SiCl provided the O-menthyl ꢀ-hydroxy-
tant influence on their biological activities. Hence,
phosphinates 2. Acidic hydrolysis of 2 gave the
the enantioselective synthesis of these compounds
corresponding ꢀ-hydroxyphosphinic acids 3. The (+)-
has attracted much attention of organic chemists [4].
enantiomer of 3a and 3b, adduct of benzaldehyde and
Three methods were involved in the synthesis of opti-
4-methylbenzaldehyde respectively, were obtained via
cally active ꢀ-hydroxyphosphonic acids via the enan-
multiple recrystallization. The absolute configuration
tioselective Pudovik reaction. Firstly, the chiral cata-
of (+)-3a was determined as S by X-ray crystallo-
lysts, such as quinine [5], chiral lewis acid containing
ꢀ
C
graphy. 2003 Wiley Periodicals, Inc. Heteroatom Chem
titanium [6], and chiral metal alkoxides [7], etc. were
used. Secondly, chiral aldehydes reacted with dialkyl
phosphite [8]. Additionally, chiral dialkyl phosphite
14:312–315, 2003; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.10150
or chiral phosphorous diamide reacted with alde-
hydes [9]. ꢀ-Hydroxyphosphinic acids are also an
important class of biologically active substance.
However, to the best of our knowledge, few reports
dealt with the synthesis of ꢀ-hydroxyphosphinic
acids.
Recently, we discovered that optically active ꢀ-
hydroxyphosphinic acids could be obtained via the
reaction of O-menthyl phenylphosphonite with aro-
matic aldehydes in presence of Me3SiCl. This inves-
tigation provided a new convenient method for the
synthesis of optically active ꢀ-hydroxyphosphinic
acids.
INTRODUCTION
ꢀ-Hydroxyphosphonic acids are compounds with
wide ranging biological activities. The addition of
compounds containing a P H bond (such as dialkyl
phosphites) to aldehydes or ketones, the Pudovik re-
action, is the most versatile pathway to these com-
pounds [1]. This reaction mainly proceedes in the
presence of a basic catalyst [2] or a metal fluoride
[3]. Only a few examples of the acid-catalyzed or
noncatalytic Pudovik reaction have been reported.
RESULTS AND DISCUSSION
Correspondence to: Chuchi Tang; e-mail: c.c.tang@eyou.com.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20002002 and 20272025.
Contract grant sponsor: Ph.D. Programs Foundation of Ministry
of Education of China.
The reaction of O-menthyl phenylphosphonite 1
with aromatic aldehydes in the presence of Me3SiCl
afforded the O-menthyl ꢀ-hydroxyphosphinates 2.
There exist two chiral centers (ꢀ-C and P) in 2. There-
fore, four diastereomers are possible. They could be
clearly observed in the 31P NMR spectra. Attempts
Contract grant sponsor: Hong Kong Polytechnic University ASD
Fund.
c
ꢀ
2003 Wiley Periodicals, Inc.
312

Convenient Synthesis of Optically Active ꢀ-Hydroxyphosphinic Acids 313
TABLE 1 Data of 2
Elemental Analysis (Calc./Found)
20
2
Ar
m.p. ( ◦C)
[α]D (c 1, CHCl3)
Yield (%)
C
H
N
a
b
c
d
e
f
C6H5
149–182
164–174
105–184
143–190
148–195
177–188
−31.1
−23.0
−42.2
−35.5
−18.0
−29.0
73.1
74.8
83.9
88.8
75.4
88.0
71.48/71.30
71.98/72.09
64.02/63.90
60.67/60.54
65.63/65.56
74.29/74.04
8.08/8.07
8.24/7.95
7.71/7.45
6.43/6.20
7.18/6.97
7.62/7.35
4-MeC6H4
3-O2NC6H4
2,4-Cl2C6H3
4-ClC6H4
3.20/3.06
2-Naphthyl
to separate the four isomers via crystallization
or column chromatography on silica gel failed.
Acidic hydrolysis of 2 provided the corresponding
ꢀ-hydroxyphosphinic acids 3, which retain only the
asymmetric ꢀ-carbon. Experimental data of 2 and 3
are summarized in Tables 1–4.
the multiply recrystallized products 3a and 3b could
be considered as a single enantiomer. From their spe-
cific rotation compared to those of the crude prod-
ucts 3a and 3b, the enantioselectivity (ee value) of
3a and 3b could be determined as 10.3% and 18.2%,
respectively. Thus only a low enantioselectivity was
realized in the reaction of 1 with aromatic aldehydes.
X-Ray crystallography was used to confirm the
configuration of the recrystallized enantiomerically
pure (+)-3a. Its molecular structure is shown in
Fig. 1. The dihedral angle between the two benzene
rings is 4.6◦. The distance of atom P to the benzene
ring plane (C(1) C(2) C(3) C(3) C(4) C(5) C(6))
The 31P NMR spectra (δ value and ratio of peak area)
of the crude products 2 were similar to those of
the products after recrystallization or column chro-
matography. The ee values of 3 could not be deter-
mined by 31P NMR spectroscopy as the addition of
a chiral amine, such as (−)-α-phenylethylamine, cin-
chonine, to transform the acid into a pair of diastere-
omeric salts did not cause a splitting of the signals.
The use of chiral HPLC or GC to separate of the two
enantiomers of acid 3 was unsuccessful. Finally, the
classic method was used to determine the enantios-
electivity of this reaction: Multiple recrystallization
of the acids 3a and 3b till their melting points and
specific rotation values were no more changed. Then
˚
is −0.0191 A. The packing diagram of (+)-3a in
a unit cell is shown in Fig. 2. The interatomic
distance for O(3) H(1) · · · O(1) (0.5-x, 1-y, 1-z) is
˚
2.748 A, which shows that there is a hydrogen bond
between O(3) and O(1) and it is also the impor-
tant force for the packing. The flack x parameter
is −0.0001 and the four groups (or atoms) con-
nected to C(7) are shown in Fig. 1, so the abso-
lute configuration of the α-carbon (C(7)) can be
determined as S [10]. CCDC 198717 contains the
supplementary crystallographic data for this pa-
per. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from
TABLE 2 NMR Data of 2
2
a
b
δ
31P
δ 1H NMR (J in Hz)
36.94, 36.66, 35.74, 34.80
36.94, 36.69, 35.97, 34.89
0.40–2.37 (m, 18H), 3.96–4.50 (m, 2H), 4.96–5.22 (m, 1H, 2 JPH = 7.89), 7.04–7.83 (m,
10H)
0.42–1.92 (m, 18H), 2.30 (d, 3H), 3.20 (br, 1H), 4.00–4.48 (m, 1H), 4.92–5.10 (m, 1H,
2 JPH = 6.26), 6.92–7.88 (m, 9H)
c
d
e
f
35.97, 35.50, 34.79, 34.05
37.50, 37.03, 35.29, 34.24
37.84, 37.22, 35.74, 34.70
36.50, 36.13, 35.60, 34.71
0.40–2.05 (m, 18H), 3.64 (br, 1H), 4.00–4.36 (m, 1H), 5.06–5.27 (m, 1H, 2 JPH = 7.20),
7.18–8.26 (m, 9H)
0.44–2.03 (m, 18H), 3.39 (br, 1H), 4.05–4.52 (m, 1H), 5.49–5.68 (m, 1H, 2 JPH = 5.22),
7.08–7.94 (m, 8H)
0.40–2.37 (m, 18H), 3.20 (br, 1H), 4.00–4.46 (m, 1H), 4.95–5.14 (m, 1H, 2 JPH = 6.26),
7.15–7.80 (m, 9H)
0.42–2.15 (m, 18H), 3.93 (br, 1H), 3.96–4.43 (m, 1H), 5.14–5.25 (m, 1H, 2 JPH = 6.26),
7.04–7.83 (m, 12H)

314 Cai et al.
TABLE 3 Data of 3
Elemental Analysis (Calc./Found)
20
3
m.p. (◦C)
[α]D (c 1, MeOH)
Yield (%)
eea (%)
C
H
N
a
b
c
d
e
f
195–199
184–188
181–185
177–180
200–204
187–190
+6.3
+11.6
+2.7
+2.6
+7.7
+4.8
79.7
58.9
87.7
46.4
84.2
36.7
10.3
18.2
62.90/63.03
64.12/64.10
53.25/53.14
49.24/49.04
55.24/55.18
68.46/68.25
5.28/5.38
5.76/5.83
4.12/3.90
3.50/3.73
4.28/4.11
5.07/5.17
4.77/4.75
aFrom the specific rotation value compared with those of multiply recrystalled enantiomeric pure (+)-3a and (+)-3b, respectively. For (+)-3a:
m.p. 210–213◦C; [α]D + 61.3 (c 1, MeOH). For (+)-3b: m.p. 197–199◦C; [α]D + 66.8 (c 1, MeOH).
20
20
the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK: fax: +44 1223
336033: or deposit@ccdc.cam.ac.uk).
phosphonite 1 and Me3SiCl for 24 h. Therefore, this
reaction seems unlikely to take place via the phos-
phonite 4. Further investigations are necessary to
interpret the mechanism of this reaction.
In contrast to the Pudovik reaction (see In-
troduction Section), in the reaction of O-menthyl
phenylphosphonite 1 with aromatic aldehydes, ba-
sic catalysts, such as Et3N, pyridine, DCM (N,Nꢁ-
dicyclohexyl-4-morpholinecaboxamidine), EtONa,
EXPERIMENTAL
1H and 31P NMR were recorded in CDCl3 or CD3OD
on a Bruker AC-P200 instrument, using TMS as an
.
and BF3Et2O could not accelerate the reaction. It
1
was found that the addition of Me3SiCl did markedly
accelerate this reaction. While the addition product
could be detected only after stirring for 24 h without
Me3SiCl, large amounts of product was formed after
0.5 h in the presence of Me3SiCl.
An acceleration effect of Me3SiCl on the Pu-
dovik reaction is not reported in the literature.
The reaction mechanism is still unclear. At first we
thought this reaction may proceed in two steps. The
first step is the formation of O-menthyl O-trimethyl-
silyl phenylphosphonite (4) via the reaction of 1 with
Me3SiCl. Then, the reaction of in situ formed phos-
phonite 4 with the aldehydes via a Abramov reaction
[11] provided the products 2. Nevertheless, no new
signal of the phosphonite 4 was observed in the 31P
NMR spectroscopy even after stirring the mixture of
internal standard for H NMR and 85% H3PO4 as
an external standard for 31P NMR. Specific rota-
tions were measured on a Perkin-Elmer 241MC po-
larimeter. Elemental analyses were conducted on a
Yanaco CHN Corder MT-3 automatic analyzer. Melt-
ing points were determined on a MP-500 melting
point apparatus. All temperatures are uncorrected.
PCl3 was used after redistillation.
Preparation of Compound 1
To a solution of (−)-menthol (46.9 g, 0.30 mol)
in 20 ml CH2Cl2 was added dropwise phenylphos-
phorous dichloride (26.9 g, 0.15 mol) at 0–5◦C un-
der nitrogen atmosphere. The resulting mixture was
stirred for 12 h at room temperature. After the re-
moval of the solvent, the crude product was dis-
tilled in vacuo to remove menthyl chloride (62–
68◦C/93 Pa). The remaining oil was the O-menthyl
TABLE 4 NMR Data of 3
20
31P
δ 1H NMR (J in Hz)
phenylphosphonite 1 (41.9 g), 99.6% yield. nD
3
a
b
c
d
e
f
δ
16
1.5154, [α]D −56.0 (c 1, THF). 31P NMR (δ, CDCl3):
2
36.47 4.74 (br, 2H), 4.87 (d, 1H, JPH = 10.82),
7.23–7.76 (m, 10H)
39.44 2.26 (s, 3H), 4.97 (br, 2H), 4.97 (d, 1H, 2 JPH
=
8.10), 7.25–7.77 (m, 9H)
2
38.18 4.90 (br, 2H), 5.17 (d, 1H, JPH = 11.34),
7.36–8.24 (m, 9H)
37.81 4.90 (br, 2H), 5.48 (d, 1H, 2 JPH = 9.73), 7.26–
7.78 (m, 8H)
2
38.77 4.90 (br, 2H), 5.02 (d, 1H, JPH = 10.71),
7.23–7.67 (m, 9H)
2
39.29 3.30 (br, 2H), 5.19 (d, 1H, JPH = 11.48),
7.30–7.89 (m, 12H)
FIGURE 1 Molecular structure of (+)-3a.

Convenient Synthesis of Optically Active ꢀ-Hydroxyphosphinic Acids 315
REFERENCES
[1] (a) Mastalerz, P. In Handbook of Organophosphorus
Chemistry; Engel, R. (Ed.); Marcel Dekker: New York,
1992; pp. 299–305; (b) Engel, R. Org React 1987, 36,
175; (c) Zimin, M. G.; Cherkasov, R. V.; Pudovik, A. N.
J Gen Chem USSR Engl Transl 1986, 56, 859.
[2] (a) Baraldi, P. G.; Guarneri, M.; Moroder, F.; Pollini,
G. P.; Simoni, D. Synthesis 1982, 653; (b) Kamber,
M.; Just, G. Can J Chem 1985, 63, 823; (c) Sasaki,
M.; Kato, T.; Yamamoto, S. J Pest Sci 1984, 9, 917;
(d) Tatsuoka, T.; Imao, K.; Suzuki, K. Heterocycles
1986, 24, 617; (e) Hammerschmidt, F. Ann 1988, 537;
(f) Hammerschmidt, F.; Voellenkle, H. Ann 1989, 577.
[3] (a) Texier-Boullet, F.; Foucauld, A. Synthesis 1982,
165; (b) Texier-Boullet, F.; Foucauld, A. Synthesis
1982, 916.
FIGURE 2 Packing diagram of (+)-3a in a unit cell.
[4] Yamagishi, T.; Yokomatsu, T.; Suemune, K.; Shibuya,
S. Tetrahedron 1999, 55, 12125.
[5] (a) Wynberg, H.; Smaardijk, A. A. Tetrahedron Lett
1983, 24, 5899; (b) Smaardijk, A. A.; Noorda, S.; Van
Bolhuis, F.; Wguberg, H. Tetrahedron Lett 1985, 26,
493.
[6] Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahe-
dron: Asymmetry 1993, 4, 1779.
21.36 (s, 51.8%), 24.56 (s, 48.2%). 1H NMR (δ, CDCl3):
0.63–2.43 (m, 18H), 4.16–4.43 (m, 1H), 7.66 (d, 1H,
1 JPH = 552 Hz), 7.36–7.93 (m, 5H). HRMS: [M+]
280.15944 (Calc. 280.15922).
[7] (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki,
M. J Am Chem Soc 1992, 114, 4418; (b) Yokomatsu, T.;
Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry
1993, 4, 1783; (c) Rath, N. P.; Spilling, C. D. Tetrahe-
dron Lett 1994, 35, 227; (d) Arai, T.; Bougauchi, M.;
Sasai, H. J Org Chem 1996, 61, 2926; (e) Sasai, H.;
Bougauchi, M.; Arai, T.; Shibasaki, M. Tetrahedron
Lett 1997, 38, 2717; (f) Yokomatsu, T.; Yamagishi, T.;
Shibuya, S. J Chem Soc, Perkin Trans 1 1997, 10,
1527.
Reaction of 1 with Aromatic Aldehydes
(General Procedure)
To a mixture of 1 (2.80 g, 10 mmol) and 3.5 ml
Me3SiCl was added dropwise aldehyde (10 mmol)
at 0◦C. The resulting mixture was stirred at room
temperature. After 1 h white floccule appeared; 2 ml
anhydrous CH2Cl2 was added and the mixture was
stirred till the aldehyde disappeared (monitored by
TLC). After the removal of the solvent, the crude
product was purified by column chromatography
(silica gel 200–300 mesh, 1:1 petroleum ether/ethyl
acetate as the eluent) to afford an oily product. Re-
crystallization from petroleum ether/ethyl acetate
(1:1) gave 2 as a white solid.
[8] Patel, D. V.; Rielly-Ganvin, K.; Ryono, D. E. Tetrahe-
dron Lett 1990, 31, 5587.
[9] (a) Koeller, K. J.; Rath, N. P.; Spilling, C. D. Phos-
phorus Sulfur Silicon 1995, 103, 171; (b) Blazis, V.
J.; Koeller, K. J.; Spilling, C. D. J Org Chem 1995,
60, 931; (c) Devitt, P. G.; Kee, T. P. Tetrahedron 1995,
51, 10987; (d) Kolodiazhnyi, O. I.; Grishkun, E. V.;
Sheiko, S.; Demchuk, O.; Thoenessen, H.; Jones, P.
G.; Schmuttler, R. Tetrahedron: Asymmetry 1998, 9,
1645.
[10] Cai, J. X.; Zhou, Z. H.; Tang, C. C. Chin J Struct Chem
2002, 21(4), 368.
Hydrolysis of 2 (General Procedure)
[11] (a) Yakomatsu, T.; Shibuya, S. Tetrahedron: Asym-
metry 1992, 3, 377; (b) Yakomatsu, T.; Yoshida, Y.;
Shibuya, S. J Org Chem 1994, 59, 7930; (c) Gordon,
N. J., Jr., S. A. E. J Org Chem 1993, 58, 5293;
(d) Sum, V.; Baird, C. A.; Kee, T. P.; Thornton-Pett, M.
J Chem Soc, Perkin Trans 1, 1994, 3183; (e) Devitt,
P. G.; Kee, T. P. J Chem Soc, Perkin Trans 1 1994, 21,
3169.
A mixture of 2 (10 mmol), 30 ml 6 N HCl, and 80 ml
1,4-dioxane was stirred at 80◦C until 2 disappeared
(monitored by TLC or 31P NMR). After the removal of
the solvent, the crude product was washed with chlo-
roform (3 × 10 ml) to provide α-hydroxyphosphinic
acids 3 as white solid.