The first separation and stereochemical determination of bis(α-hydroxyalkyl) phosphinic acids diastereoisomers

Article abstract of DOI:10.1016/j.tetlet.2005.09.081

A separation of bis(α-hydroxyalkyl) phosphinic acid diastereoisomers is described. A novel method for the determination stereochemistry of bis(α-hydroxyalkyl) phosphinic acid diastereoisomers has been developed. The stereochemistry of one diastereoisomer

Full text of DOI:10.1016/j.tetlet.2005.09.081

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7955–7957
The first separation and stereochemical determination
of bis(a-hydroxyalkyl) phosphinic acids diastereoisomers
Babak Kaboudin* and Hamideh Haghighat
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-1159, Iran
Received 19 July 2005; revised 1 September 2005; accepted 14 September 2005
Available online 3 October 2005
Abstract—A separation of bis(a-hydroxyalkyl) phosphinic acid diastereoisomers is described. A novel method for the determination
stereochemistry of bis(a-hydroxyalkyl) phosphinic acid diastereoisomers has been developed. The stereochemistry of one diastereo-
isomer was confirmed after converting to the corresponding methyl ester using trimethyl orthoformate.
Ó 2005 Published by Elsevier Ltd.
a-Functionalized phosphinic acids are valuable inter-
mediates for the preparation of medicinal compounds
and synthetic intermediates.1–4 Among the a-functional
phosphinic acids, a-hydroxyphosphinic acids are an
important class of compounds that exhibit a variety of
interesting and useful properties.5–10 In recent years,
the preparation of a-hydroxyphosphinic acids has
attracted attention due to their biological activities with
broad applications as enzyme inhibitors or as dinucleo-
tide analogues having antiviral properties.11 In addition,
they are useful intermediates in the synthesis of other
phosphorus compounds.12,13 These compounds may
also be used as precursors for the synthesis of organo-
phosphorus polymers possessing flame-resistant, corro-
sion-resistant and ion-exchange properties.14,15 Indeed,
a-hydroxyphosphinic acids are used as extractants for
the recovery or separation of some metal ions.16 As part
of our efforts to explore the use of microwave-assisted
reactions for the synthesis of organophosphorus com-
pounds,17 we recently described a new method for the
preparation of bis(a-hydroxyalkyl) phosphinic acids
from the reactions of hypophosphorous acid with alde-
hydes using microwave irradiation, which produces high
yields of bis(a-hydroxyalkyl) phosphinic acids.18 In con-
trast to the widely studied separation and stereochemical
determination of a-hydroxyphosphonic acid diastereo-
mers,19 we did not find any report on the separation
and structure determination of bis(a-hydroxyalkyl)
phosphinic acid diastereoisomers. Herein, we report
the first method for the separation and determination
of stereochemistry of bis(a-hydroxyalkyl) phosphinic
acid diastereoisomers.
We carried out the reaction of benzaldehyde with hypo-
phosphorus acid under microwave irradiation to afford
bis(a-hydroxyphenylmethyl) phosphinic acid in 82%
yield after 0.5 min. 31P NMR spectrum of 2a exhibited
two peaks at d 38.74 and 36.59 ppm due to the diastereo-
isomers. 1H NMR spectrum of 2a exhibited two
doublets at d 5.14 and 4.84 ppm indicative of HC-P cou-
pling (JHP = 7.4 Hz). Due to the presence of two stereo-
genic carbons bonded to the phosphorus atom, and the
phosphorus atom itself being a pseudo-asymmetric cen-
ter,20 these compounds exist as three diastereomeric
forms: two meso (syn) and one racemic pair (anti). How-
1
ever, 31P and H NMR spectra exhibit degeneracies due
to the rapid prototopic transfer of the acidic proton
between the phosphoryl (P@O) and acidic (P–OH) sites
and only two signals are observed, corresponding to the
racemic form R,R/S,S and the meso (R,S). We found
that when the reaction mixture was subjected to washing
with nonpolar and polar solvents, only one diastereomer
was extracted using methanol (Schemes 1 and 2).
O
P
OH
O
H
C
MW
R
C
H
R
2 R CHO
H
+
H
P
0.5-2 min
OH OH
Keywords: Phosphinic acids; Stereochemistry; Microwave; Trimethyl
OH
orthoformate.
2
1
*
Corresponding author. Tel.: +98 241 4153220; fax: +98 241
4249023; e-mail: kaboudin@iasbs.ac.ir
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.09.081

7956
B. Kaboudin, H. Haghighat / Tetrahedron Letters 46 (2005) 7955–7957
OH
H
H
OH
OH OH
H
H
H
OH
Ph
HO
Ph
H
H
H
HO
Ph
OH
Ph
Ph
P
P
Ph
Ph
P
Ph
P
OH
O
O
OH
O
HO
HO
O
R,R
S,S
R,S
S,R
Syn
Anti
Scheme 2.
H
H
H
H
H
OH
O
P
OH
HO
Ph
OH
Ph
HO
Ph
OH
Ph
HO
Ph
H
H
C
HC(OCH3)3
MW, 10 min
Ph
C
H
Ph
P
P
P
Ph
OCH3
OCH3
O
OHOH
O
H3CO
O
Syn
Anti
Scheme 3.
Redmore, D. In Topics in Phosphorus Chemistry; Griffith,
E. J., Grayson, M., Eds.; Wiley: New York, 1976; Vol. 8.
The stereochemistry of this diastereoisomer was con-
firmed after converting to the corresponding methyl
ester using trimethyl orthoformate under microwave
irradiation for 10 min.21 This reaction failed after 24 h
without microwave irradiation. The syn methyl ester
would be formed as a mixture of two diastereoisomers,
due to the new stereogenic center at the phosphorus
atom, whilst the anti as a dl pair would have only
one stereoisomer. 31P NMR spectrum of the methyl
ester exhibited only one major peak at d 44.98 ppm
(Scheme 3). On the other hand, 13C NMR of the
methyl ester exhibited two doublet peaks at 68.3 and
69.0 for two C–P groups. On the basis of these results,
the diastereoisomer assigned as the anti. On the other
hand, methylation of a mixture of the two diastereo-
meric bis(a-hydroxyphenylmethyl) phosphinic acids
showed three peaks in 31P NMR spectrum due to the
three diastereomeric forms, the syn and anti diastereo-
mers (Scheme 3).
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Further investigations on this reaction are now in
progress.
Acknowledgements
The Institute for Advanced Studies in Basic Sciences
(IASBS) is thanked for supporting this work.
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wave was used in all experiments). After irradiation, 50 ml
of ethyl acetate was added and the reaction mixture was
stirred for 5 min. n-Hexane (50 ml) was added to this
mixture and a white powder precipitated. The precipitated
bis(a-hydroxyalkyl)phosphinic acid was filtered. For the
separation of diastereoisomers, a simple washing with
nonpolar to polar solvents (n-hexane to EtOAc) then
washing with methanol (300 mL), gave the anti-diastereo-
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21. New procedure for the synthesis of methyl bis(a-hydroxy-
phenylmethyl) phosphinate: A suspension of bis(a-hydr-
oxyphenylmethyll)phosphinic acid (0.556 g, 0.002 mol)
and trimethyl orthoformate (5 ml excess) was irradiated
with microwaves for 10 min (step-by-step) at 180 W. The
mixture became homogeneous as it was irradiated by
microwaves. Volatile compounds were removed in vacuo
and then 5 ml of acetone was added to the reaction
mixture and stirred for 5 min. n-Hexane (50 ml) was added
to this mixture and white powder was precipitated. The
precipitated methyl bis(a-hydroxyphenylmethyll)phosphi-
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gel with n-hexane-ethyl acetate (9:1 to 1:9) and evapora-
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product as white crystals in a 65% (0.38 g) yield. Methyl
bis(a-hydroxyphenylmethyl) phosphinate: mp 172–174 °C
(n-hexane–dichloromethane); 1H NMR (CD3SOCD3/
TMS-500 MHz): 2.95 (d, 3H, J = 9.4 Hz), 5.21 (2H, d,
J = 6.9 Hz), 6.21–6.42 (br, OH), 7.2–7.45 (10H, m);
31P-NMR (CD3SOCD3/H3PO4): 44.98 ppm; 13C NMR
(CD3SOCD3/TMS-125.7 MHz): 52.2 (d, JPC = 7.5 Hz),
68.3 (d, JPC = 65.7 Hz), 69.0 (d, JPC = 72.3 Hz), 127.4,
127.6, 127.8, 128.1, 128.2, 138.2 (d, JPC = 2.9 Hz), 138.3
(d, JPC = 2.9 Hz). Anal. Calcd for C15H17O4P. C, 61.64;
H, 5.82. Found: C, 61.38; H, 5.73.
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30 mmol of benzaldehyde and the mixture irradiated with