Synthesis of optically active hydroxyphosphonates

Article abstract of DOI:10.1002/hc.20391

The reduction of dimenthyl ketophosphonates with sodium borohydride involves asymmetric induction at the a-carbon atom, resulting in a small excess of the (R)-enantiomer of the a-hydroxyphosphonate formed. A higher ee purity was achieved if the reduction

Full text of DOI:10.1002/hc.20391

Heteroatom Chemistry
Volume 19, Number 2, 2008
Synthesis of Optically Active
Hydroxyphosphonates
Irina Guliaiko,1 Vitaly Nesterov,1 Sergei Sheiko,1
Oleg I. Kolodiazhnyi,1 Matthias Freytag,2 Peter G. Jones,2
and Reinhard Schmutzler2
1Institute of Bioorganic Chemistry, National Academy of Sciences,
Murmanskaia Street, 1, 02094 Kiev, Ukraine
2Institut fu¨ r Anorganische und Analytische Chemie, Technische Universita¨t,
Hagenring 30, 38106 Braunschweig, Germany
Received 22 March 2007; revised 19 June 2007
INTRODUCTION
ABSTRACT: The reduction of dimenthyl ketophos-
phonates with sodium borohydride involves asym-
metric induction at the α-carbon atom, resulting
in a small excess of the (R)-enantiomer of the α-
hydroxyphosphonate formed. A higher ee purity was
achieved if the reduction of chiral dimenthyl ke-
tophosphonates was carried out by the chiral complex
of NaBH4-L-proline, owing to the double asymmet-
ric induction at the α-carbon atom. The hydroxy-
phosphonates obtained were isolated in a diastere-
omerically pure state and were transformed to the
optically active, free hydroxyalkylphosphonic acids.
The (R)-configuration of one of them was proved by X-
α-Hydroxyphosphonates and α-phosphonic acids
possess important biological activity through the
inhibition of a number of enzymes, and the ab-
solute configuration at the α-position of substi-
tuted phosphonic acids has been shown to influence
their biological properties significantly [1–3]. While
enantioselective syntheses of α-aminophosphonic
acids have been studied extensively [4], the synthe-
sis of enantiomerically pure α-hydroxyphosphonates
has not yet developed sufficiently [5–8]. The pre-
viously employed methods provide access to many
α-hydroxyphosphonates, but the use of chiral aux-
iliaries and/or catalysts is required to improve the
stereoselectivity of these methods [9]. A possible
method for the stereoselective introduction of the
hydroxyl group is a stereoselective reduction of
prochiral keto compounds. Reductions with chirally
modified metal hydrides, catalytic hydrogenation in
the presence of chiral metal complexes, asymmetric
hydrosilylation, hydroboration, etc. are widely used
for their preparation.
ꢀ
C
ray crystal structure analysis. 2008 Wiley Periodicals,
Inc. Heteroatom Chem 19:133–139, 2008; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20391
In this article, we describe the synthesis of opti-
cally active α-hydroxyphosphonic acids by reduction
of dimenthyl α-ketophosphonates 1. The resulting
α-hydroxyphosphonates can easily be purified by
crystallization, and can, after removal of the men-
thyl groups, be transformed to the corresponding
optically active α-hydroxyphosphonic acids.
Correspondence to: Irina Guliaiko; e-mail: oikol123@rambler.ru;
Reinhard Schmutzler; e-mail: r.schmutzler@tu-bs.de.
Contract grant sponsor: Deutsche Forschungsgemeinschaft
(DFG).
c
ꢀ
2008 Wiley Periodicals, Inc.
133

134 Guliaiko et al.
RESULTS AND DISCUSSION
The initial α-ketophosphonates 1 were prepared by
two procedures: one-step reaction of tris(1R,2S,5R)-
menthylphosphite with aroyl chlorides (Method a)
and by a two-step procedure (Method b) that com-
prises preparation of α-hydroxyphosphonates by the
reaction of di-(1R,2S,5R)-menthylphosphite with
aldehydes followed by their conversion without iso-
lation and purification to ketophosphonates 1 in
high yields (90%–100%) by treatment with the pyri-
dinium dichromate/trimethylchlorosilane oxidizing
system [10].
The ketophosphonates prepared by the first
method (Method a) were purified by column
chromatography and were isolated in satisfac-
tory yields (60%–80%), Thus, the reaction of 4-
fluorobenzoyl chloride with trimenthylphosphite
proceeded smoothly at room temperature in toluene,
affording α-ketophosphonate 1b in 80% yield
(Scheme 1).
SCHEME 2
from acetonitrile provided stereochemically pure
(R)-distereomers (Scheme 2). The stereoselectivity
was reversed when the reduction was performed in
THF, leading to the preferential formation of the (S)-
diastereomer.
We succeeded in improving the stereoselec-
tivity of ketophosphonate reduction by using the
chiral complex of sodium borohydride with nat-
ural L-proline (NaBH4-Pro). For the preparation
of this reducing reagent, an equimolar amount of
L-proline was added to sodium borohydride sus-
pended in THF, and the mixture was stirred at room
temperature for several hours [11]. The ketophos-
phonate was then added to NaBH4-Pro, resulting
in the formation of (S)-hydroxyphosphonate with a
stereoselectivity in the range from 75% to 80% de
purity. Compounds (S)-2a–c were crystallized from
hexane and isolated in approximately 100% optical
purity (Scheme 3)
The chiral menthyl groups of 2a–c were
cleaved off under mild conditions by a modified
procedure of Morita et al. [12]. The reaction of
the dimenthyl α-hydroxyphosphonates 2a–c with
trimethylsilyl chloride and NaI in acetonitrile led to
bis(trimethysilyl)-α-hydroxyphosphonates, which
were finally hydrolyzed in a mixture of water/ethanol
to afford the optically active α-hydroxyphosphonic
acids 3a–c (Scheme 4). The treatment of
α-hydroxyphosphonates 2a–c with hydrochlo-
ric acid in water/dioxane solution also gave the
The chemical purity and yields of ketophospho-
nates 1 prepared by Method b were considerably
higher than by Method a, achieving 90% yield or
more. Therefore, the ketophosphonates prepared by
this procedure were used in transformations without
further purification.
The structure of compounds 1 has been con-
1
firmed by H and 31P NMR spectroscopy. 31P NMR
spectra reveal a singlet in the region δP = −3.1 to −3.3
ppm. 1H NMR spectra display signals for the protons
of the menthyl group as well as the aromatic protons
of the expected multiplicity and intensity.
The treatment of α-ketophosphonates 1 with
sodium borohydride in ethanol proceeded with
moderate stereoselectivity to afford a mixture of
(R)- and (S)-diastereomers, with higher contents of
the corresponding (R)-hydroxybenzylphosphonates.
The crystallization of (R)-α-hydroxyphosphonates
SCHEME 1
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Optically Active Hydroxyphosphonates 135
31P NMR spectra of compounds 2a–c show sig-
nals for the two diastereomers, with δP values in the
region 21.0–21.5 ppm, The downfield signal belongs
to the (R)-diastereomer and the upfield signal to the
(S)-diastereomer of α-hydroxyphosphonates 2.
1H NMR spectra of compounds 2a–c revealed
that the signals belong to the protons of the menthyl
group, aromatic protons of appropriate multiplicity
and intensity, a broad signal due to the OH group
at δH = 3.7 ppm, and a CH doublet at δH = 4.9 ppm.
1H and 13C NMR spectra of compounds 2a–c indi-
cate that the molecules are asymmetric, because the
signals of the two menthyl groups bonded to phos-
phorus are magnetically nonequivalent.
The
configuration
of
(R)-(+)-α-hydroxy-
SCHEME 4
benzylphosphonic acid (2a) was confirmed by
comparing its optical rotation with literature
data [8]. The configuration of the newly formed
stereogenic center in the major diastereomer of
compound 2b was established as R by single crystal
X-ray structure analysis. The structure of 2b is
shown in Fig. 1. The coordination at phospho-
rus is distorted tetrahedral, with angles between
102.88(5)◦ (O4 P C1) and 113.82(6)◦ (O1 P C1);
the largest angles, as usual, involve the phosphoryl
oxygen atom. The P O bond lengths are: P O1:
147.16(10) pm; P O3: 158.01(8) pm, and P O4:
156.91(9) pm.
corresponding free optically active phosphonic
acids 3a–c in good yields. Owing to the steric
hindrance of the esters 2a–c, it was necessary to use
longer reaction times and higher temperatures.
Similarly, α-hydroxyphosphonates 2a–c were
prepared by phospha-aldol addition of aromatic
aldehydes to dimenthylphosphite as shown in
Scheme 5 [9,13]. The reaction was performed at
room temperature in the absence of solvent, with 1,8-
diazabicyclo[5.4.0]undecene (DBU) as the catalyst,
and according to a method described by us earlier
[9] to give a mixture of (R)- and (S)-diastereomers
of α-hydroxyphosphonates 2a–c, which were pu-
rified by crystallization from hexane to give (R)-
diastereomers of 100% de purity. Compounds 2a–
c were identical to (R)-hydroxyphosphonates pre-
pared by the reduction of ketophosphonates with
sodium borohydride (Scheme 5).
Very short (H· · ·O: 194(2) pm) and linear
(O H· · ·O: 169.6(18)◦) intermolecular hydrogen
bonds between the hydroxyl hydrogen and the phos-
phoryl oxygen link the molecules to form chains par-
allel to the y axis.
1
Compounds 2 and 3 were identified by H, 13C,
and 31P NMR spectroscopy and liquid chromatogra-
phy. Dimenthyl α-hydroxyphosphonates are easily
crystallizable compounds, which are obtained in a
stereochemically pure state.
FIGURE 1 Molecular structure of di-(1R,2S,5R)-menthyl-
(R)-1-hydroxy-1-(o-methoxyphenyl) methylphosphonate 2b in
the crystal.
SCHEME 5
Heteroatom Chemistry DOI 10.1002/hc

136 Guliaiko et al.
tive to 85% H3PO4 as an external standard. All ma-
nipulations were carried out under argon, solvents
were distilled in an inert atmosphere from the dry-
ing agents listed in parentheses: diethyl ether, hex-
ane, heptane, benzene, tetrachloromethane (P2O5),
methanol, triethylamine (sodium), and ethyl acetate
(calcium chloride). Pyridinium dichromate was ob-
tained from ACROS. Dimenthylphosphite was pre-
pared according to the method of Kolodiazhnyi et al.
[14].
HPLC separations were carried out on the
“Milichrom-1A” instrument (Russia). Silasorb DEA,
column 120 mm × 2 mm (hexane/isopropanol mix-
ture in a 95:5 ratio as eluent); Silasorb C-18, column
120 mm × 2 mm (50% aqueous acetonitrile as elu-
ent); UV detector, λ = 260 nm. Column chromato-
graphy was performed using Silicagel L 100/160.
Optical rotations were measured on a Perkin-
Elmer Model 241 spectropolarimeter. Melting points
are uncorrected.
FIGURE 2 Facial attack on the α-phenylketophosphonate
carbonyl group by NaBH4 (left) and NaBH4-Pro (right).
The preferential formation of (R)-diastereomers
observed in the reduction of α-ketophosphonates 1
with NaBH4 in ethanol can be anticipated to some
extent by examining their molecular models. The
molecular structures of α-ketophosphonate 1a and
α-hydroxyphosphonate 2b indicate the high asym-
metry of the molecules owing to a propeller-like
arrangement of the menthyl groups around the phos-
phorus atom. Thus, one can make the reasonable
assumption that the attack of the reducing agent
on the carbonyl group will take place preferentially
from the side leading to the (R)-configuration rather
than from the opposite side, which is shielded by
the menthyl group (Fig. 2, left). This corresponds
to an approach to the more exposed face of the α-
ketophosphonate.
The selectivity of the reduction with NaBH4-Pro
depends upon the geometry of the complex formed
by coordination of the carbonyl oxygen to the boron
atom and of the carboxylic sodium to the oxygen
of the P O group. The reaction cycle inside the fa-
vored intermediate complex is shown in Fig. 2, right.
It is evident that in this case the attack of the chi-
ral reducing agent on the carbonyl group will take
place preferentially from the side leading to the (S)-
configuration rather than the opposite Re side.
In summary, the described asymmetric reduc-
tion of dimenthyl α-ketophosphonates provides an
easy route to both stereoisomers of optically ac-
tive α-hydroxyphosphonic acids in good yield and
in enantiomeric excess. The reduction of dimen-
thyl ketophosphonates with NaBH4 led preferably
to the formation of (R)-α-hydroxyphosphonates,
whereas the reduction with NaBH4-Pro furnishes
(S)-hydroxyphosphonates.
Di-(1R,2S,5R)-menthyl-benzoylphosphonate
(1a)
Method a. A solution of benzoyl chloride (1.41
g, 10 mmol) in 5 mL of toluene was added to a
solution of tris(1R,2S,5R)-menthylphosphite (4.96
g, 10 mmol) in 10 mL of toluene with cooling
(−20◦C), and the reaction mixture was left to stand
overnight. The solvent was evaporated, and the
menthyl chloride formed was removed in vacuo
(0.02 mmHg). The product obtained was purified by
column chromatography on silica gel (hexane/ethyl
acetate = 4:1 as eluent), TLC: Rf = 0.3 (hexane/ethyl
acetate = 4.5:1).
Yield: 2.8 g (60%). [α]2D0 −62 (c 1.5, CHCl3).
Calcd. for C27H43O4P: P, 6.70%. Found: P, 6.61%.
1H NMR (CDCl3): δ = 0.7–1.0 (m, CH3); 1.1–2.2 (m,
CH2 + CH); 4.15 (dt, OCH, JHH 2.3, JHH 4.1); 7.35 (m,
C6H5); 7.45 (m, C6H5). 31P NMR (CDCl3): δP = −3.5.
Method b. Trimethylchlorosilane (0.6 g, 5.5
mmol) was added to a pyridinium dichromate
(1.68 g, 4.47 mmol) solution in 30 mL of methy-
lene chloride with stirring at 0◦C, and then dimen-
thyl α-hydroxyphosphonate, prepared from dimen-
thylphosphite (6.3 g, 1.75 mmol) and benzaldehyde
(1.86 g, 1.75 mmol) was added. The reaction mixture
was stirred at room temperature until completion of
the reaction (∼4 h), filtered through silica gel, and
washed with a small amount of ethyl acetate. After
evaporation, a colorless liquid thus obtained was pu-
rified by column chromatography.
EXPERIMENTAL
All the experiments were carried out with exclu-
sion of air and moisture. Solvents were purified and
dried according to the usual methods. NMR spec-
tra were recorded on a BRUKER AC-200 spectro-
meter with working frequencies of 200 MHz (1H)
and 81 MHz (31P), respectively. All 1H chemical shifts
are reported in δ (ppm) relative to Me4Si as an inter-
nal standard. 31P NMR spectra were recorded, rela-
Yield: 95%, R 0.3 (hexane/ethyl acetate = 4:1).
f
[α]2D0 62 (c 1.5, CHCl3). Calcd. for C27H43O4P:
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Optically Active Hydroxyphosphonates 137
P, 6.70%. Found: P, 6.61%. 1H NMR (CDCl3),
δ = 0.7–1.0 (m, CH3); 1.1–2.2 (m, CH2 + CH); 4.15
(dt, OCH, JHH 2.3, JHH 4.1); 7.35 (m, C6H5). 31P NMR
(CDCl3), δP = −3.5.
benzaldehyde according to the above-mentioned
method.
Yield: 50%; mp 139◦C. [α]2D0 −70 (c 1, toluene).
The compounds 2a prepared by Methods a and
b were identical.
Calcd. for C27H45O4P: P, 6.27%. Found: P, 6.15%.
1H NMR (CDCl3): δ = 0.7–1.0 (m, CH3); 1.1–1.23 (m,
CH2 + CH); 3.7 (br, OH); 4.2 (dt, OCH, JHH 2.3, JHH
4.1); 4.92 (d, CHP, JHP 11); 7.2–7.3 (m, C6H5); 7.3–
7.5 (m, C6H5). 13C NMR: δ = 127.99 (d, J 2.5); 127.8
(d, JCP 2.5); 127.3 (d, C6H5, JCP 9.6); 71.6 (d, PC, JCP
160); 48.6 (d, CHOa, JCP 14); 48.5 (d, CHOb, JCP 13.2);
45.66, s; 42.53, s; 34, s; 31.5, s; 25.31, s; 22.7, s; 21.97,
s; 21.13, s; 21.03, s; 15,74, 15.60 (diastereotopic men-
thyl groups). 31P NMR (CDCl3), δP = 23.71.
Di-(1R,2S,5R)-menthyl-o-
methoxybenzoylphosphonate(1b)
Compound 1b was prepared by analogy with com-
pound 1a. The product was purified by column chro-
matography (hexane/ethyl acetate as eluent).
Yield: 75%. Calcd. for C28H45O5P: P, 6.29%.
1
Found: P, 6.39%. H NMR (CDCl3): δ = 0.7–1.0 (m,
CH3); 1.1–2.2 (m, CH2 + CH); 3.9 s (OCH3); 4.15 (dt,
OCH, JHH 2.3, JHH 4.1); 6.6–6.8 (m, C6H4); 7.0–7.2 (m,
C6H4). 31P NMR (CDCl3): δP = −3.6.
Di-(1R,2S,5R)-menthyl-(S)-1-phenyl-1-
hydroxymethylphosphonate((S)-2a)
Di-(1R,2S,5R)-menthyl-2-
fluorobenzoylphosphonate(1c)
Method a. To a suspension of sodium borohy-
dride (0.045 g, 1.19 mmol) in 8 mL of THF, L-proline
(0.137 g, 1.19 mmol) was added. The mixture was
stirred at room temperature for 6 to 12 h. Ketophos-
phonate 1a (0.368 g, 0.795 mmol) was then added,
and the mixture was stirred for further 24 h at room
temperature. The solvent was evaporated and 10 mL
of water/ethyl acetate (1:1) mixture was added to
the residue. The organic layer was separated and the
aqueous layer was extracted with ethyl acetate. The
extract was washed with 1N HCl, then with sodium
carbonate solution, again with water, and finally
dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure to give the
crystalline solid.
Method a. As in the case of 1a, the product was
purified by column chromatography (hexane/ethyl
acetate as eluent).
Yield: 80%. [α]2D0 −72 (c 1, toluene). H NMR
1
(CDCl3): δ = 0.6–0.9 (m, CH3); 0.8–2.0 (m, CH2 + CH);
4.0 (dt, OCH, JHH 2.3, JHH 4.1); 7.4 (m, C6H4); 7.43
(m, C6H4). Calcd. for C27H42FO4P: P, 6.44%. Found:
P, 6.38%. 31P NMR (CDCl3): δP = −3.1.
Method b. Prepared similarly to compound 1a.
R 0.74 (hexane/ethyl acetate = 5:1).
f
Yield: 90%. [α]2D0 72 (c 1, toluene). Calcd. for
1
C27H42FO4P: P, 6.38%. Found: P, 6.44%. H NMR
(CDCl3), δ = 0.6–0.9 (m, CH3); 0.8–2.0 (m, CH2 + CH);
4.0 (dt, OCH, JHH 2.3, JHH 4.1); 7.4 (m, C6H4). 31P
NMR (CDCl3), δP = −3.1.
Yield: 0.367
g
(70%); mp 112◦C–113◦C.
[α]2D0−87.6 (c 1.3, CHCl3). Calcd. for C27H45O4P:
1
P, 6.67%. Found: P, 6.38%. H NMR (CDCl3): δ =
1.01 (d, CH3, JHH 6.9); 1.04 (d, CH3, JHH 6.9); 1.08 (d,
CH3, JHH 6.9); 1.18 (d, CH3, JHH 6.9); 1.20 (d, CH3,
Di-(1R,2S,5R)-menthyl-(R)-1-phenyl-1-
hydroxymethylphosphonate((R)-2a)
JHH 6.9); 1.21 (d, CH3, JHH 6.9); 1.40–2.6 (m, CH and
3
CH); 2.00 [m, CH(CH3)2]; 2.4 [m, CH(CH3)2]; 4.49
(m, OCH); 5.2 (d, CHP, JHH 10.5); 5.10 (br, OH); 7.48
(m, ArH); 7.8 (m, ArH). 31P NMR (CDCl3), δP = 22.3.
Method a. Sodium borohydride (0.456, 1.2
mmol) was added to a solution of α-ketophospho-
nate 1a (4.5 g, 1.0 mmol) in 20 mL of ethanol. Af-
ter the reaction mixture was left overnight, the sol-
vent was evaporated. The residue was dissolved in
diluted hydrochloric acid and extracted with methy-
lene chloride (2 × 20 mL). The solution was filtered,
the solvent was evaporated, and the remaining prod-
uct was recrystallized from hexane or acetonitrile.
Yield: 2.5 g (45%); mp 139◦C. [α]D20 −70 (c 1,
toluene). 31P NMR (CDCl3), δP = 23.71
Di-(1R,2S,5R)-menthyl-(R)-1-(o-methoxyphenyl)-
1-hydroxymethylphosphonate((R)-2b)
The preparation was as described for compound 2a.
The product was purified by crystallization from hex-
ane and acetonitrile.
Yield: 70%; mp 138◦C. [α]2D0 −56.4 (c 1, toluene).
Calcd. for C28H47O5P: P, 6.27%. Found: P, 6.25%.
1H NMR (CDCl3): δ = 0.7–1.0 (m, CH3); 1.1–1.23 (m,
CH2 + CH); 3.4 (br, OH); 3.55 (s, OCH3); 4.0 (dt,
OCH, JHH 2.3, JHH 4.1); 5.17 (d, CHP, JHP 11);
Method b. Hydroxymethylphosphonate 2a was
prepared from di-(1R,2S,5R)menthylphosphite and
Heteroatom Chemistry DOI 10.1002/hc

138 Guliaiko et al.
6.6–6.8 (m, C6H4); 7.0–7.2 (m, C6H4). 13C NMR
(CDCl3): δ = 157.10 (d, J 6.5); 129.00 (d, J 2.8); 128.8
(d, JCP 2.8); 125.3 (d, JCP 5.5); 120.6 (d, JCP 2.0); 110.5,
128.8 (d, JCP 2.0, C6H5); 66.7 (d, PC, JCP 161); 55
(s, CH3O); 48.8 (d, CHOa JCP 35); 48.5 (d, CHOb,
JCP 34); 43.8, s; 34.09, s; 33.9, s; 31.5, s; 25.24, s;
22.7, s; 21.97, s; 21.87, s; 21.21, s; 21.05; 15,72, 15.62
(diastereotopic menthyl groups). 31P NMR (CDCl3),
δP = 21.49.
was placed in a flask and 25 mL of 6N hydrochlo-
ric acid was added. The reaction mixture was then
left for 3 days at 80◦C. The hydrolysis was moni-
tored by 31P NMR spectroscopy. When the reaction
was complete, the solvent was evaporated under re-
duced pressure, the residue was dissolved in ethanol,
followed by the excess addition of cyclohexylamine
(∼1.5 ml). The precipitate of the dicyclohexylammo-
nium salt was collected by filtration.
Method b. In a round-bottomed flask, NaI (4
equiv.) and trimethylchlorosilane (4 eqiv.) were
added to a solution of α-hydroxyphosphonates
3a–c (1 equiv.) in CH3CN (10 mL), and the re-
sulting mixture was refluxed for 12 h. The sodium
chloride that was precipitated was filtered off. Af-
ter removal of the solvent under reduced pressure,
a solution of ethanol (3 mL) and H2O (2.5 mL)
was added, and the resulting mixture was stirred at
room temperature for 2 h. The organic layer was
separated and the water phase was evaporated in
vacuo.
Di-(1R,2S,5R)-menthyl-(S)-1-hydroxy-1-(2-
methoxyphenyl)methylphosphonate ((S)-2b)
Yield: 74%; mp 116◦C–117◦C. [α]2D0 −75.2 (c 0.66,
CHCl3). Calcd. for C28H47O5P: C, 67.99%; H, 9.58%;
P, 6.26%. Found: C, 68.16%; H, 9.50%; P, 6.27%. 1H
NMR (C6D6): δ = 0.60 (d, CH3, 3 JHH 6.9); 0.52 (d, CH3,
3 JHH 6.9); 0.73 (d, CH3, 3 JHH 6.9); 0.79 (m, 2CH3); 0.84
3
(d, CH3, JHH 6.9); 0.92–1.54 (m, CH2 and CH); 2.14
[m, CH(CH3)2]; 2.40 [m, CH(CH3)2]; 3.59 (s, OCH3);
4.17 (m, OCH); 4.03 (m, OCH); 4.54 (br, OH); 5.24 d
(1H, CHP, JHH 13.2); 6.59 d (1H, ArH, JHH 8.1); 6.80
(t, 1H, ArH, JHH 7.9); 7.04 (t, 1H, ArH, JHH 7.9); 7.60
(d, ArH, JHH 7.5). 31P NMR (CDCl3), δP = 21.13.
Yield: 50%; mp 226◦C. [α]2D0 +14.0 (c = 1, 50% aque-
ous MeOH) corresponding to the (R)-configuration
of acid 3a.
The hydroxyphosphonic acid was dissolved in
ethanol, and excess cyclohexylamine was added to
obtain a solid precipitate, which was purified by
crystallization.
Di-(1R,2S,5R)-menthyl-(R)-1-(2-fluorophenyl)-
1-hydroxymethylphosphonate((R)-2c)
The preparation was as described for compound 2a.
The product was purified by crystallization from hex-
ane and acetonitrile.
(+)-(R)-2α-Cyclohexylammonium
salt:
mp
>200◦C. [α]2D0 +24.0 (c = 1, CHCl3).
Yield: 65%; mp 135◦C. [α]2D0 −68.9 (c 1, toluene).
1H NMR (DMSO): δ = 0.6–0.9 (m, CH3); 0.95–1.98
(m, CH2 + CH); 5.95 (br, OH); 4.05 (dt, OCH, JHH
2.3, JHH 4.1); 4.75 (d, CHP, JHP 11); 7.05 (m, C6H5);
7.45 (m, C6H5). 31P NMR (CDCl3), δP = 21.53.
(–)-(S)-1-Phenyl-1-hydroxymethylphosphonic
Acid ((S)-3a)
Yield: 50%; mp 226◦C. [α]2D0 −14.0 (c = 1, 50% aque-
ous MeOH) corresponding to the (S)-absolute con-
figuration of acid 3a.
Di-(1R,2S,5R)-menthyl-(S)-1-(2-fluorophenyl)-
1-hydroxymethylphosphonate ((S)-2c)
(–)-(S)-2α-Cyclohexylammonium
salt:
mp
>200◦C. [α]D20 −24.0 (c = 1, CHCl3). The dicyclohexyl-
ammonium salt of (–)-(S)-phenyl(hydroxymethyl)-
phosphonic acid has been described elsewhere
[8].
Yield: 97%; mp 137.5◦C–138.5◦C. [α]2D0 −83.7 (c 1.3,
CHCl3). Calcd. for C27H44FO4P: P, 6.42%. Found: P,
1
3
6.38%. H NMR (C6D6): δ = 0.71 (d, CH3, JHH 6.9);
3
3
0.76 (d, CH3, JHH 6.9); 0.86 (d, CH3, JHH 6.9); 0.91
(d, CH3, JHH 6.9); 1.00–2.25 (m, CH3 and CH); 1.74
3
[m, CH(CH3)2]; 2.0 [m, CH(CH3)2]; 4.04 (d, CHP, JHH
22.5); 4.2 (m, OCH), 5.18 (br, OH); 6.9 (t, JHH 8.2,
C6H4); 7.45 (m, C6H4). 31P NMR (CDCl3), δP = 19.8.
(+)-(R)-1-(o-Methoxy)phenyl-1-
hydroxymethylphosphonic Acid (R)-3b
The preparation was as described for compound 3a.
The product was purified by crystallization from hex-
ane and acetonitrile.
(+)-(R)-3b-(Cyclohexylammonium salt). Yield:
50%. mp >200◦C. [α]D20 +30.0 (c = 1, CHCl3). 31P
NMR (CDCl3), δP = 17.0
(+)-(R)-1-Phenyl-1-hydroxymethylphosphonic
Acid ((R)-3a)
Method a. A solution of hydroxymethylphos-
phonate 2a (1 g, 2 mmol) in 50 mL of dioxane
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Optically Active Hydroxyphosphonates 139
center (Tele/fax: Int. +12-23-33-60-33; e-mail: de-
X-ray Crystal Structure Determination of (R)-2b
posit@ccdc.cam.ac.uk).
Crystal data: C28H47O5P, M = 494.63. Crystal
size 0.46 mm × 0.19 mm × 0.17 mm; mono-
clinic, P21; a = 1256.95(12) pm, b= 548.37(6) pm,
c= 2087.1(2) pm; β = 100.406(3)◦; U = 1.4149(2)
nm3; Z = 2; µ = 0.131 mm−1; Dx = 1.161 mg/m3;
T = −130◦C.
REFERENCES
[1] Hildebrand, R. L.; Henderson, T. O.; in: The Role of
Phosphonates in Living Systems; Hildebrand, R. L.
(Ed.); Chemical Rubber Company: Boca Raton, FL,
1983; pp. 5–29.
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[5] Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 2005,
16, 3295–3340.
Reflections: total 22,952 to 2θ = 60◦, unique
8210 (Rint = 0.0355). Final wR2 = 0.0855, R1 =
0.0350 for 318 parameters and 1 restraint; S= 0.999,
max ꢀρ = 0.342 e nm−3.
[6] Blazis, V. J.; Koeller, K. J.; Spilling, C. D. Tetrahe-
dron: Asymmetry 1994, 5, 499–502.
[7] Blazis, V. J.; Koeller, K. J.; Spilling, C. D. J Org Chem
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[8] (a) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J Org
Chem 1995, 60, 6656–6657; (b) Sasai, H.; Bougauchi,
M.; Aral, T.; Shibasaki, M. Tetrahedron Lett 1997, 38,
2717–2720.
Data collection and reduction: The crystal was
mounted on a glass fiber in inert oil and transferred
to the cold gas stream of the diffractometer (Bruker
SMART 1000 CCD with LT-3 low temperature at-
tachment; monochromated Mo Kα radiation).
Structure solution and refinement: The struc-
ture was solved by direct methods and refined
anisotropically on F2 (program system: SHELXL-
97, G.M. Sheldrick, University of Go¨ttingen). Hy-
drogen atoms were included using a riding model
or rigid methyl groups, except for the hydroxyl hy-
drogen, which was found and refined freely. The
Flack parameter refined to −0.01(5). Full details
(excluding structure factors) have been deposited
at the Cambridge Crystallographic Data Centre, 12
Union Rd., GB-Cambridge CB2 1EZ, under the pub-
lication no. CDC-180997. Copies may be obtained
free of charge on application to the director of the
[9] Kolodiazhnyi, O. I.; Grishkun, E. V.; Sheiko, S.;
Demchuk, O.; Thoennessen, H.; Jones, P. G.; Schmut-
zler, R. Russ Chem Bull 1999, 48, 1588–1593.
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[12] Morita, T.; Okamoto, Y.; Sakurai, H. Tetrahedron
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[13] Kolodiazhnyi, O. I.; Grishkun, E. V.; Sheiko, S.
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Demchuk, O.; Thoennessen, H.; Jones, P. G.; Schmut-
zler, R. Tetrahedron: Asymmetry 1998, 9, 1645–1647.
Heteroatom Chemistry DOI 10.1002/hc