Enantioselective reduction of ketophosphonates using chiral acid adducts with sodium borohydride

Article abstract of DOI:10.1134/S1070363206070048

A method for asymmetric reduction of α-and β-ketophosphonates using a chiral complex prepared from sodium borohydride and D-or L-tartaric acid is developed. Reduction of α-or β-ketophosphonates by these reagents led to formation of corresponding (S)-or (R

Full text of DOI:10.1134/S1070363206070048

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 7, pp. 1022 1030.
Pleiades Publishing, Inc., 2006.
Original Russian Text V.V. Nesterov, O.I. Kolodyazhnyi, 2006, published in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 7, pp. 1068 1077.
Enantioselective Reduction of Ketophosphonates
Using Chiral Acid Adducts with Sodium Borohydride
V. V. Nesterov and O. I. Kolodyazhnyi
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine,
ul. Murmanskaya 1, Kiev 02094, Ukraine
Received November 25, 2005
Abstract A method for asymmetric reduction of - and -ketophosphonates using a chiral complex
prepared from sodium borohydride and D- or L-tartaric acid is developed. Reduction of - or -ketophos-
phonates by these reagents led to formation of corresponding (S)- or (R)-hydroxyphosphonates. Reduction of
chiral di(1R,2S,5R)-menthylketophosphonates by the chiral complex NaBH4/(R,R)-tartaric acid due to the
dual compliant asymmetric induction resulted in increased stereoselectivity of the reaction and led to forma-
tion of the hydroxyphosphonates with ee 90% or higher. On the other hand, reduction of di(1R,2S,5R)-methyl-
ketophosphonates by the chiral complex NaBH4/(S,S)-tartaric acid proceeded as non-compliant dual asym-
metric induction and resulted in decreased reaction stereoselectivity leading to formation of hydroxyphos-
phonates with 45 60% ee. The developed methodology was applied to the synthesis of (R)-phosphocarnitine
in multigram amounts.
DOI: 10.1134/S1070363206070048
Hydroxyphosphinic acids comprise an important
class of compounds whose representatives are widely
distributed in the nature [1 3]. Some of these com-
pounds possess interesting physiological properties
being antibacterial, antiviral and anticancer prepara-
tions, antibiotics, ferment inhibitors, aminoacid
mimetics and pesticides [2].
are too complicated to be reproduced. By this reasons,
in continuation of our studies on application of
available natural compounds as the reagents in
asymmetric synthesis [9, 10], we attempted to find
simple procedures for the reduction of the ketophos-
phonates with chiral reagents prepared on the basis of
sodium borohydride and the chiral acids such as tar-
taric acid or proline.
Some of compounds are used in clinics for treating
different diseases. Although existing methods allow
ease preparation of racemic hydroxyphosphonates,
synthesis of chiral compounds of this class remains a
complicated synthetic challenge and commonly
requires specific approach in a particular case. Note
that most of the earlier developed procedures require
application of hardly available reagents and catalysts
[4, 5].
OH
(RO)2P(O)(CH2)n
O
H
R
(RO)2P(O)(CH2)n
R
H
I
II
n = 0, 1.
The initial -ketophosphonates I were prepared by
two procedures: one-step reaction of trialkyl phosphites
with aroyl chlorides (method a) and by two-step pro-
cedure (method b), which comprise preparation of
racemic -hydroxyphosphonates by reaction of dialkyl
phosphites with aldehydes followed by their conver-
sion in high yield (90 100%) without isolation and
purification to ketophosphonates II at the treatment
using pyridinium bichromate trimethylchlorosilane
oxidizing system. The ketophosphonates prepared by
the method a were purified by column chromato-
graphy and isolated with satisfactory yields (60 80%).
For example, reaction of 4-fluorobenzoyl chloride
with trimenthyl phosphite in toluene proceeded
smoothly at room temperature resulting in formation
of -ketophosphonate II in 70% yield.
In this communication we describe asymmetric
synthesis of the optically active - and -hydroxy-
phosphonates II and acids by reduction of related
ketophosphonates I. The asymmetric reduction of
ketophosphonates has been studied earlier. It included
reduction with borane or catecholborane in the pre-
sence of chiral oxazaborolydine catalysts [6], reduc-
tion with chiral chlorodiisopynacampheylboranes [7]
and enantioselective hydrogenation in the presence of
chiral BINAP ruthenium(II) catalyst [8] (BINAP =
2,2 -bis(diphenylphosphino)-1,1 -binaphthyl). However
all these methods require application of expensive
reagents and specific reaction conditions which often
1022

ENANTIOSELECTIVE REDUCTION OF KETOPHOSPHONATES
1023
O
RO
O
RO
R
O
R
H
Py2Cr2O7
Me3SiCl
R COCl
P
P
(RO)3P
(RO)2P(O)H + R CHO,
a
b
OH
RO
RO
Ia If
IIa IIf
R = Et, R = Ph (a); R = (1R,2S,5R)-Mnt, R = Ph (b), C6H4F-2 (c), C6H4OMe-2 (d), piperonyl (e), i-Pr (f).
Chemical purity and yield of the ketophosphonates
prepared by the method b is considerably higher than
a, achieving 90% and more. Therefore the ketophos-
phonates prepared by this procedure were used in
further transformations without purification.
with butyllithium to form carbanion IV followed by
the reaction with carboxylic acid chlorides or methyl
esters. Diminishing in the effect of the permetallation
reaction on the final result was achieved by addition
of cuprous bromide to the reaction mixture for con-
version of the lithium derivative IV into cuprous
derivative V.
The -ketophosphonates were synthesized from
dialkyl methylphosphonates III by reaction in THF
R
O
P
Cu2X2
R COCl
BuLi
(RO)2P(O)CH2Cu
(RO)2P(O)Me
(RO)2P(O)CH2Li
O
RO
III
IV
V
OR
VI
X = Br, I; R = Et, R = Ph (a), CH2Cl (b).
Reduction of the dimenthyl ketophosphonates with
sodium borohydride in ethanol led to (R)- -hydroxy-
phosphonates in a low stereoselectivity (30 35% de)
and yield [11]. In THF reduction of dimenthyl keto-
phosphonate proceeded with higher yield but stereo-
selectivity remained low. The (S)-hydroxyphospho-
nates obtained could be purified by crystallization
from acetonitrile and isolated stereochemically pure.
(depenting on the initial reagent ratio) is assigned are
well known and are used as reducing reagents in
organic synthesis [14].
NaBH4 + (HOOCC*HOH)2
{Na[B(OOCC*HOH)2]} 0.5OC4H8.
Reduction of ketophosphonates with that reagent
was performed at cooling to 30 C in THF (method
a). Reduction of diethyl -ketophosphonates with the
sodium borohydride (R,R)-tartaric acid chiral reagent
yielded diethyl (1S)- -hydroxybenzylphosphonates
with optical purity 60%, while reduction of dime-
thyl ketophosphonates led to formation of (1S)- -
hydroxybenzylphosphonates I with diastereomeric
purity up to 80 93%. The higher stereoselectivity of
reduction in the case of dimenthyl arylketophospho-
nates we explain by the effect of dual asymmetric
induction [15], because here the asymmetric induc-
tions due to menthyl groups supplementes that of
tartaric acid. At the same time, reduction of dimenthyl
ketophosphonates with the sodium borohydride (S,S)-
tartaric acid reagent resulted in lower stereoselectivity.
For example, reduction of dimenthyl 1-oxobenzylphos-
phonate yielded corresponding hydroxyphosphonate
with 45% de only. It is obviously that asymmetric
inductions due to (1R,2S,5R)-menthyl groups and
(R,R)-tartaric acids are compatible and therefore are
We succeeded in improvement of the stereoselec-
tivity of ketophosphonate hydroborination when used
chiral complex of sodium borohydride with natural
(R,R)-(+)-tartaric acids [12,13]. This reducing reagent
was prepared by mixing sodium borohydride with
tartaric acids in 1:1 ration in THF followed by reflux-
ing the mixture. After removing the solvent the target
compound could be isolated as a colorless fine crystal-
line substance with high melting point (>250 C). The
compound is very hygroscopic and reacts with water.
It contains coordinatively bonded THF (0.5 equv.) as
1
confirmed by H NMR spectrum which contains a
multiplet at 1.7 ppm (CH2C), a multiplet at 3.7 ppm
(CH2O) and a multiplet at 4.5 ppm (CHOH). Detailed
study of structure is restricted due to its low solubility
in ordinary organic solvents. Note that compounds
obtained by treatment of sodium borohydride with
achiral carboxylic acids (acetic or trifluoroacetic) to
which structure of Na[BH(OAc)3] or Na[BH2(OAc)2]
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 7 2006

1024
NESTEROV, KOLODYAZHNYI
O
O
R
H
R
H
NaBH4/(R,R)-( )-TA
NaBH4/(S,S)-(+)-TA
RO
Ia, Ib
RO
RO
P
P
OH
OH
OR
(S)-IIa, IIb
(R)-IIa, IIb
Here and hereinafter: TA is tartaric acid.
Table 1. Stereoselectivity of reduction of ketophospho-
nates Ia and Ib
menthyl groups and (S,S)-tartaric acid act in opposite
directions and diminish resulting stereoselectivity
(Table 1).
Compound
Type of
stereo-
Tartaric acid
configuration
R
ee
II
Stereochemistry of reduction of - and -keto-
phosphonates with sodium borohydrid tartaric acid
reagent depends on the absolute configuration of tar-
taric acid. With the reagent prepared from (R)-tartaric
acid the reaction results in formation of (S- -hydroxy-
phosphonates, while the reagent from (S)-tartaric acid
configuration selectivity
Et
Et
Mnt
R,R
S,S
R,R
63
62
92.5
S
R
S
Singular
Dual,
compliant
Dual,
gives (R)- -hydroxyphosphonates. Reduction of
ketophosphonates VI with the sodium borohydride
-
Mnt
S,S
46
R
opposite
(R)-tartaric acid reagent also led to -hydroxyphos-
phonates (S)-VII, while with the sodium borohyd-
ride (S)-tartaric acid reagent to -hydroxyphospho-
nates (R)-VII.
summated and increase the total stereoselectivity. On
the other hand, asymmetric inductions of (1R,2S,5R)-
R
R
O
O
P
NaBH4/(R,R)-TA
NaBH4/(S,S)-TA
P
VIa,
VIb
H
RO
O
RO
O
H
OR
OR
(2S)-VIIa
(2R)-VII
Insofar as reduction of ketophosphonates with the
complex NaBH4/(R,R-tartaric acid affords (S)-hydroxy-
phosphonates, it is very probable that P=O group is
involved to the transition state leading to formation
of hydroxyphosphonates as it shown in Fig. 1, and
promotes stereofacial attack of carbonyl group by
hydride ion from the Si side.
HO
H
High stereoselectivity was revealed also by the
sodium borohydride complex with (L)-proline (me-
thod b). For its preparation, to sodium borohydride
suspended in THF was added equimolar amount of
(L)-proline and the mixture was stirred at room
temperature for several hours. Then to the such
generated chiral complex a ketophosphonate was
added, and this resulted in formation of an (S)-hyd-
roxyphosphonate. Compounds IIa, IIb, and also VIIb
were isolated with stereoselectivity 60 70%.
O
O
O
O
H
O
H
O
Si
H
P
B
OR
H
RO
O
R
O
R
NaBH4/(L)-proline
Re
Ia, Ib
RO
RO
(S)-IIa, IIb
P
H
Fig. 1. MOPAC-8 stereochemical modeling of reduction
of ketophosphonate with NaBH /(R,R)-tartaric acid
OH
4
reagent.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 7 2006

ENANTIOSELECTIVE REDUCTION OF KETOPHOSPHONATES
1025
Table 2. Asymmetric reduction of ketophosphonates by sodium borohydride tartaric acids complex to hydroxyphos-
phonates
Tartaric acid
configuration
Comp. no.
n
Yield, %
[ ]2D0, deg
c
Configurationa
ee (R : S)
IIa
IIa
0
0
0
0
0
0
0
0
1
1
95
94
95
98
97
96
97
97.6
95
82
R,R
S,S
R,R
S,S
R,R
R,R
R,R
R,R
R,R
R,R
15.4
+28.3
87.6
70.0
83.7
75.2
74.0
82.8
25.0
12.4
2.6
2.1
1.3
1.0
1.3
1.0
1.0
2.2
2.4
3.2
S
R
S
R
S
S
S
S
R
S
2: 8b
8: 2c
3.8: 96.2
73: 27
9.8: 90.1
13: 87
98: 2
IIb
IIb
IIc
IId
IIe
IIf
VIIa
VIIb
84: 16
28: 72c
9: 1c
a
b
Configuration of the predominating enantiomer was found from comparison of the measured values with published data. Deter-
31
c
31
mined by means of P NMR spectra after derivatization with dimenthyl chlorophosphite. Determined by means of P NMR
spectra with quinine as chiral solvating reagent.
Diethyl -hydroxyphosphonates were purified
rolysed to free hydroxyphosphonic acids whose
configuration was determined earlier [16 23].
by column chromatography. Dimenthyl -hydroxy-
phosphonates were obtained enantiomericaly pure
after crystallization from acetonitrile (Table 2).
The developed procedure for reduction of the keto-
phosphonates we applied to the synthesis of phos-
phocarnitine XI.
Several methods were used for elucidation optical
purity of the synthesized compounds. The diastereo-
isomeric ratio of hydroxyphosphonate dimenthyl
esters was registered by 31P {1H} NMR spectroscopy
directly. In the case of homochiral diethyl hydroxy-
phosphonates the optical purity was determined after
derivatization with di-(1R,2S,5R)-menthyl chloro-
phosphite (I) resulted in formation of diastereomers
of the derivatives with a significant difference in
(R)-Carnitine possess important biological pro-
perties and is used in pharmacology as an important
component for -oxidation of fatty acids: it performs
transport of the fatty acids in mytohondrial membrane.
A great attention was paid to the modificated car-
nitines, in part, the phosphocarnitine, synthesized
earlier by means of chemoenzymatic methods. Un-
fortunately, information on the properties of the
prepared representatives of the phosphocarnitine are
contradictory and inconsistent with one another.
Mikolajczyk and coworkers described (S)-phospho-
carnitine as an oil with optical rotation angle [ ]D20
24 (c 2.3, MeOH H2O) [18]. Wroblewski described
the same compound as a solid fine crystalline sub-
stance, mp 270 C and [ ]2D0 17.4 (c 1.15, H2O) [21],
and Yuan and Wang as a substance with [ ]2D0 15 (c
2.1, H2O) [25]. This discrepancy arises probably due
to small amounts (milligrams) of the phosphocarnitine
synthesized. Therefore we performed first synthesis
of (R)-phosphocarnitine by ordinary chemical pro-
cedure through asymmetric reduction of correspond-
ing diethyl 2-ketophosphonate [17].
chemical shifts
in 31P NMR spectra, which pro-
vided accurate iPntegration of signals and correct
measuring of their diastereomeric ratio [12].
Et3N
(MntO)2PCl + II
(MntO)2P O CH(R)P(O)(OEt)2
For determination of optical purity of diethyl hyd-
roxyphosphonates we found convenient to use natural
quinine as a chiral solvating reagent. In this case the
signals of the hydroxyphosphonate (R)- and (S)-enan-
tiomers in 31P {1H} NMR spectra were separated up to
zero line and could be easily measured by integration.
The absolute configuration of dimenthyl hydroxy-
phosphonates was determined by the method of che-
mical extrapolation. The dimenthyl esters were hyd-
O
O
R
R
H
H3O+
We also developed a multigram procedure for the
synthesis (R)-phosphocarnitine by means of enantio-
selective hydroborination of diethyl 2-keto-3-chloro-
propylphosphonate VI.
P
H
P
HO
HO
RO
RO
OH
OH
II
VIII
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 7 2006

1026
NESTEROV, KOLODYAZHNYI
O
OH
H
BuLi
ClCH2COCl
NaBH4/(R,R)-TA
(EtO)2P(O)Me
(EtO)2P(O)
(EtO)2P(O)
Cl
Cl
Cu2X2
VIb
(S)-VIIb, 80% ee
OH
H
OH
OH
Me3SiBr
+
Me3N
+
(HO)( O)(O)P
H2O3P
NMe3
(HO)2(O)P
NMe3
Cl
H2O/EtOH
H2O
Me3N HCl
H
Cl
H
(S)-IX
(R)-X
(R)-XI
X = Br, I.
In the first step, diethyl 3-chloro-2-oxopropylphos-
phonate (VIb) was prepared from available diethyl
methylphosphonate. Then by enantioselective reduc-
tion of -ketophosphonate VI we prepared optically
active diethyl 3-chloro-2-hydroxypropylphosphonate
(VI), the precursor of phosphocarnitine (XI). Enan-
tiomeric purity of compound VIIb, 80% ee, was
measured by means of 31P NMR spectroscopy with
dimenthyl chlorophosphite as a derivatizating reagent
and quinine as a chiral solvating reagent. The 31P
NMR spectrum of VIIb with quinine contains two
by us is a crystalline compound decomposed at heat-
ing above 250 C.
1
The H NMR spectra of -hydroxyphosphonates
are of special interest. They disclose signals of dia-
stereotopic protons in PCH2 and CH2X groups as
doublet doublets due to spin-spin coupling with phos-
phorus atom, proton of CHOH group (vicinal constan
2
3JHH), and due to mutual coupling JHH. The NMR
spectra allows to perform conformational analysis of
the obtained compounds. Phosphocarnitine and 2-hyd-
signals,
29.4 and 29.11 ppm, in the ratio 90:10
roxy-3-chloropropylphosphonate
probably
exist
(reductionPby the method a) or 19.7:80.3 (method b)
The values of optical purity in parallel measurements
coincided. Then VIIb was dealkylated with trimethyl-
bromosilane followed by treating by aqueous alcohol
to free phosphonic acid IX and then treated by water
solution of trimethylamine. The chloride VII thus was
converted into trimethylammonium salt X which in
the reaction course was dehydrochlorinated to form
trimethylammonium chloride and phosphocarnitine as
betain XI. The product was isolated from the reaction
mixture by column chromatography on silica gel. Pure
(R)-phosphocarnitine was obtained in high yield with
good optical purity. Structure of compound XI was
confirmed by elemental analysis and NMR spec-
troscopy. The (R)-phosphocarnitine (XI) synthesized
mainly as trans conformers at the C1 C2 bond (Fig.
2a), as follows from the values of vicinal constants
3
3
3JHP 18 Hz and geminal constants JH
1aH2
1bH2
and JH
equal to 15 18 Hz and 6.3 8.0 Hz, respectively. In
the molecules of -hydroxyphosphonates probably
there is an intramolecular hydrogen bond between
hydrogen atom of CH OH group and P=O group, in
consistence with the downfield shift of the signal of
hydroxyl proton to 4.7 5 ppm. Stability of the
trans conformers probably is higher due to formation
six-membered ring with conformation approaching
chair form (Fig. 3). In the phosphocarnitine molecule
(a)
(b)
O
O
(RO)(R O)P
H
H
H
O
O
X
H
P(O)(OR)(OR )
H
H
H
H
CH2X
Fig. 2. Conformational analysis of -hydroxyphospho-
+
nates: (a) Newman projection at
C
C
bond,
+
Fig. 3. MM conformation with the energy minimum of
(b) Newman projection at C C bond. X= Cl, Me N .
phosphocarnitine.
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 7 2006

ENANTIOSELECTIVE REDUCTION OF KETOPHOSPHONATES
Table 3. Conformations of -hydroxyphosphonates VII, XI
Experimentf (by NMR spectra)
1027
Calculation (MM+)
HC2 C3H angle HC1 C2H angle HC2 C3H angle
Comp. no.
3JHH, Hz HC1 C2H angle
3JHH, Hz
VII
XI
3.6
9
6.6
6.9
47.50
171.25
25.88
6.9
6.3
1.2
9.5
28.38
146.33
65.34
180
69.69
176.21
72.59
54.39
78.56
50.81
150.38
176.08
176.08
this intramolecular hydrogen bond is probably es-
pecially strong, as follows from even greater down-
field shift of the signal of OH proton, to 5 5.1 ppm,
because in this case it involves negatively charged
oxygen atom in P O group.
The bond C2 C3 in phosphocarnitine and 2-hyd-
roxy-3-chloropropylphosphonate molecules, is prob-
ably in staggered cisoid conformation as follows from
and then racemic dimenthyl -hydroxyphosphonate
prepared from 1.75 mol of dimenthyl phosphite and
1.75 mol of benzaldehyde. The reaction mixture was
stirred at room temperature to the reaction completing
(2 4 h), filtered through silica gel and washed with
small amount of ethyl acetate. After evaporation a
colorless liquid obtained was purified by column
chromatography. Yield 95%, Rf 0.3 (hexane ethyl
acetate, 4:1). [ ]2D0 62 (c 1.5, CHCl3). 1H
NMR spectrum (CDCl3), , ppm (J, Hz): 0.7 1.0 m
(CH3); 1.1 2.2 m (CH2 + CH); 4.15 d.t (OCH, JHH
2.3, JHH 4.1); 7.35 m (C6H5); 31P NMR spectrum
(CDCl3), , ppm: 2.3. Found, %: P 6.61. C27H43O4P.
Calculated, %: P 6.70.
2aH3
small values of vicinal constants: JH
6.9 Hz and
2bH3
JH
6.3 Hz
Modeling the molecule by MM+ calculation allow
to reveal values of dihedral angles in energetically
most preferable conformations of the molecules of
hydroxyphosphonates VIIb and XI (Fig. 3) [26]. The
theoretically calculated values well correspond to the
experimental values of the dihedral angles obtained
from the data of NMR spectra by calculation with the
Karplus equation [27], confirming our conclusions
(Table 3).
Di(1R,2S,5R)-( )-menthyl 2-fluorobenzoyl
phosphonate (Ic). Prepared similarly to compound
Ia. Rf 0.74 (hexane:ethyl acetate = 5:1). Yield 90%.
[ ]2D0 72 (c 1, toluene). H NMR spectrum NMR
1
(CDCl3), , ppm, (J, Hz): 0.6 0.9 m (CH3); 0.8 2.0 m
(CH2 + CH); 4.0 d.t. (OCH, JHH 2.3, JHH 4.1); 7.4 m
(C6H4). 31P NMR spectrum (CDCl3): P, ppm: 3.1.
Found, %: P 6.44 C27H42FO4P. Calculated, %: P 6.38.
EXPERIMENTAL
Melting points are not corrected. NMR spectra
were registered on a Varian VXR-300 instrument at
300 (1H) and 126.16 (31P) MHz with internal TMS
(1H) and external 85% H3PO4 in D2O (31P). Optical
rotation angles were measured on a Polax-2L polari-
meter (Japan).
Di(1R,2S,5R)-( )-menthyl 2-methoxybenzoyl
phosphonate (Id). Prepared similarly to compound
Ib. Yield 96%, The product was purified by column
chromatography. Rf 0.33 (hexane ethyl acetate,
1
4:1). H NMR spectrum NMR (CDCl3), , ppm (J,
Hz): 0.7 1.0 m (CH3); 1.1 2.2 m (CH2 + CH); 3.9 s
(OCH3); 4.15 d.t (OCH, JHH 2.3, JHH 4.1); 6.6 6.8 m
(C6H4); 7.0 7.2 m (C6H4). 31P NMR spectrum
(CDCl3), P, ppm: 3.5. Found, %: P 6.25. C28H45
O5P. Calculated, %: P 6.39.
Column chromatography was performed with
Merck 60 silica gel. All experiments were performed
in inert atmosphere (Ar). For the reaction anhydrous
solvents were used: THF was freshly distilled over
sodium in the presence of benzophenone, methylene
chloride was distilled over P4O10. The Fluka tartaric
acids, sodium borohydride and menthol were used.
Tartaric acids and sodium borohydride priory to use
were kept for 2 h in a vacuum at 30 C.
Di(1R,2S,5R)-( )-menthyl piperonoylphos-
phonate (Ie). Prepared similarly to compound Ib.
Yield 82%, Rf 0.51 (eluent hexane ethyl acetate, 4:1).
1
[ ]2D0 63.8 (c 5.48, CHCl3). H NMR spectrum
Di(1R,2S,5R)-( )-menthyl benzoylphosphonate
(Ib). To pyridinium bichromate (1.68 g, 4.47 mmol)
in 30 ml of methylene chloride with stirring was
added trimethylchlorosilane (0.6 g, 5.5 mmol) at 0 C,
(CDCl3), , ppm, (J, Hz): 0.7 1.0 m (CH3); 1.1
2.2 m (CH2 + CH); 4.15 d.t (2H, JHH 2.3, JHH 4.1,
OCH); 5.8 s (2H, OCH2O); 6.75 d (1H, J 10); 7.23 s
(1H); 7.66 s (1H); 8.25 d (1H, C6H4, J 10). 31P NMR
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 7 2006

1028
NESTEROV, KOLODYAZHNYI
spectrum (CDCl3), P, ppm: 1.8. Found, %: P 6.14.
C28H45O6P. Calculated, %: P 6.09.
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 12 h. Then to the mixture
ketophosphonate (0.368 g, 0.795 mmol) was added
and stir was continued for 24 h. Then solvent was
evaporated and 10 ml of water ethyl acetate (1:1)
mixture was added to the residue. Organic layer was
separated and aqueous layer was extracted with ethyl
acetate. The extract was washed with 1 N HCl, then
with sodium carbonate solution, again with water, and
died over anhydrous sodium sulfate. Solvent was
evaporated. Yield 0.367 g (70%), mp 112 113, [ ]D20
87.6 (c 1.3, CHCl3). 1H NMR spectrum (CDCl3), ,
ppm (J, Hz): 1.01 d (3H, CH3, JHH 6.9); 1.04 d (3H,
CH3, JHH 6.9); 1.08 d (3H, CH3, JHH 6.9); 1.18 d (3H,
CH3, JHH 6.9); 1.20 d (3H, CH3, JHH 6.9); 1.21 d (3H,
CH3, JHH 6.9); 1.40 2.6 m (14H, CH3 and CH); 2.00
m [1H, CH(CH3)2]; 2.4 m [1H, CH(CH3)2]; 4.49 m
(2H, OCH); 5.2 d (1H, CHP, JHH 10.5); 5.10 br (1H,
OH); 7.48 m (3H, ArH); 7.8 m (2H, ArH). 31P NMR
spectrum (CDCl3), P, ppm: 22.3. Found, %: P 6.38.
C27H45O4P. Calculated, %: P 6.67.
Di(1R,2S,5R)-( )-menthyl 2-methylpropionyl-
phosphonate (If). Prepared similarly to compound Ia.
Yield 86%, Rf 0.73 (eluent hexane ethyl acetate,
10:1). [ ]2D0 90.4 (c 0.75, CHCl3). H NMR spec-
1
trum (CDCl3), , ppm (J, Hz): 0.7 1.0 m (CH3); 1.1
2.2 m (CH2 + CH); 3.15 m (1H, CHCH3); 4.2 d.t
(OCH, JHH 2.3, JHH 4.1). 31P NMR spectrum (CDCl3),
P, ppm): 3.4. Found, %: P 7.04. C25H47O4P. Cal-
culated, %: P 7.00.
Diethyl (S)-hydroxy(phenyl)methylphosphonate
(IIa). To sodium borohydride (7.16 mmol) in 25 ml
of THF L-(+)-tartaric acid (7.16 mmol) was added and
the reaction mixture was refluxed for 4 h. The mixture
was cooled to 30 C, ketophosphonate (1.79 mol) in
8 ml THF was added to it while stirring and the mix-
ture was left overnight for 24 h at 30 C. Then 15 ml
of ethyl acetate was added and 25 ml of 1 N hydro-
chloric acid was added dropwise. Organic layer vas
separated and aqueous layer was extracted twice with
ethyl acetate. Combined organic extracts were washed
with saturated solution of sodium carbonate and dried
over Na2SO4. Solvent was removed in a vacuum and
residue was recrystallized from acetonitrile. Yield
95%, mp 74 76 C, [ ]2D0 15.4 (c 2.6, CHCl3).
1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.21 t
(3H, CH3, JHH 7.1); 1.26 t (3H, CH3, JHH 7.1); 3.8 br
(1H, OH); 3.90 4.13 m (4H, 2CH2); 5.01 d (1H, CH,
JPH 10.9); 7.3 7.38 m (3H, ArH); 7.49 d (2H, ArH).
31P NMR spectrum (CDCl3), , ppm: 22.00 (cor-
respondence with [19, 20]).
Di[(1R,2S,5R)-( )-menth-2-yl] (S)-hydroxy-(2-
fluorophenyl)methylphosphonate (IIc). Prepared
similarly to compound IIa. Yield 97%, mp 137.5
138.5 C, [ ]2D0 83.7 (c 1.3, CHCl3). H NMR spec-
1
trum (CDCl3), , ppm(J, Hz): 0.71 d (3H, CH3, JHH
6.9); 0.76 d (6H, CH3, JHH 6.9); 0.86 d (6H, CH3, JHH
6.9); 0.91 d (3H, CH3, JHH 6.9); 1.00 2.25 m (14H,
CH3 and CH); 1.74 m [1H, CH(CH3)2]; 2.0 m [1H,
CH(CH3)2]; 4.04 d (1H, CHP, JHH 22.5); 4.2 m (2H,
OCH); 5.18 br (1H, OH); 6.9 t (3H, JHH 8.2, ArH);
7.45 m (2H, ArH). 31P NMR spectrum (CDCl3),
,
P
Diethyl (R)-hydroxy(phenyl)methylphosphonate
(IIa). Prepared similarly from sodium borohydride,
(S,S-( )-tartaric acid and ketophosphonate Ia in THF.
Yield 94%, mp 74 76 C, [ ]2D0 +28.32 (c 2.1,
CHCl3), corresponding to the data for the compound
described earlier [22].
ppm: 19.8. Found, %: P 6.38. C27H44FO4 P. Calcu-
lated, %: P 6.42.
Di[(1R,2S,5R)-( )-menth-2-yl] (S)-hydroxy-(2-
methoxyphenyl)methylphosphonate (IId). Prepared
similarly to compound IIa. Yield 74%, mp 116
1
117 C, [ ]2D0 75.2 (c 0.66, CHCl3). H NMR spec-
Di[(1R,2S,5R)-( )-Menthyl] (S)-1-phenyl-1-
hydroxymethylphosphonate (IIb). a. To sodium
borohydride (4 mmol) in 15 ml of THF L-(+)-tartaric
acid (4 mmol) was added and the reaction mixture
was refluxed for 4 h. The mixture was cooled to
30 C, ketophosphonate (0.99 mol) in 5 ml of THF
was added and the mixture was left for 24 h at 30 C.
Then to the mixture 8 ml of ethyl acetate was added
and 20 ml of 1 N hydrochloric acid was added drop-
wise. Organic layer was separated and aqueous layer
was extracted with ethyl acetate. Solvent was removed
in a vacuum and residue was recrystallized from
acetonitrile, mp 112 113. Yield 80%.
trum (C6D6), , ppm: (J, Hz): 0.60 d (3H, CH3, JHH
6.9); 0.52 d (3H, CH3, JHH 6.9); 0.73 d (3H, CH3, JHH
6.9); 0.79 m (6H, 2CH3); 0.84 d (3H, CH3, JHH 6.9);
0.92 1.54 m (14H, CH2 and CH); 2.14 m (1H, CH
(CH3)2); 2.40 m (1H, CH(CH3)2); 3.59 (3H, OCH3);
4.17 m (1H, OCH); 4.03 m (1H, OCH); 4.54 br (1H,
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 (1H, ArH, JHH 7.5). 31P NMR spec-
trum (CDCl3), P, ppm: 20.98. Found, %: P 6.27.
C28H47O5P. Calculated, %: P 6.26.
( )-[(1R,2S,5R)-Menth-2-yl]-(R)-hydroxy
(2-methoxyphenyl)methylphosphonate (R)-(IId).
b. To a suspension of sodium borohydride (0.045 g, Prepared similarly to compound R-IIa. The product
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 7 2006

ENANTIOSELECTIVE REDUCTION OF KETOPHOSPHONATES
1029
was purified by recrystallization from hexane or
( )-(S)-hydroxy(phenyl)methylphosphonic acid di-
ciclohexylammonium salt has been described [16].
acetonitrile. Yield 50%, mp 138 C, [ ]2D0 56.4 (c 1,
1
toluene). H NMR spectrum (CDCl3), , ppm (J, Hz):
Diethyl (S)-2-hydroxy-2-phenylethylphospho-
nate (VIIa). Yield 95%, [ ]2D0 25 (c 2.38, CHCl3).
1H NMR spectrum (C6D6), , ppm (J, Hz): 1.10 t (3H,
CH3, JHH 6.9); 1.11 t (3H, CH3, JHH 6.9); 1.90
2.12 m (2H, CH2); 3.77 3.99 m (4H, 2CH2); 4.75 br
(1H, OH); 4.96 5.06 m (1H, CHOH); 7.05 t (1H, ArH,
JHH 7.2); 7.14 t (2H, ArH, JHH 7.2 ); 7.28 d (2H, ArH,
JHH 7.2). 31P NMR spectrum (CDCl3), P, ppm: 29.6,
which corresponds to the earlier described compound
[22, 23].
0.7 1.0 m (CH3); 1.1 1.23 m (CH2 + CH); 3.4 br
(OH); 3.55 s (OCH3); 4.0 d.t (OCH, JHH 2.3, JHH 4.1);
5.17 d (CHP, JHP 11); 6.6 6.8 m (C6H4); 7.0 7.2 m
(C6H4). 31P NMR spectrum (CDCl3), P, ppm: 21.49.
Found, %: P 6.27. C28H47O5P. Calculated, %: P 6.26.
Di[(1R,2S,5R)-( )-menth-2-yl] (S)-hydroxy-
(piperonyl)methylphosphonate
(IIe).
Prepared
similarly to compound IIa. Yield 70%, mp 96 C,
[ ]2D0 74 (c 1, CHCl3). 1H NMR spectrum (CDCl3),
, ppm (J, Hz): 4.09 m (2H, OCH), 4.7 d (1H, CHP,
JHH 10.5); 5.38 ¼ (1H, OH); 5.65 s (2H, CH2O2);
6.57 d (1H, ArH, JHH 7.9); 6.85 d (1H, ArH, JHH 7.9);
6.98 s (1 H, ArH). 31P NMR spectrum (CDCl3), ,
ppm: 19.8. Found, %: P 6.26 C30H49O6P; Calculated,
%: P: 5.77.
Diethyl 2-oxo-3-chloropropylphosphonate
(VIb). To a solution of butyllithium (1.7 N,
0.077 mol) at stirring and cooling to 78 C was added
consecutively 50 ml of THF and a solution of
0.07 mol of diethyl methylphosphonate in 25 ml of
THF. After 20 min stirring 0.077 mol of Cu2Br2 was
added to the mixture and stir was continued for 1.5 h
at 60 to 40 C. Then 0.073 mol of chloroacetyl
chloride in 30 ml of ether was added, stir was con-
tinued for 1.5 h at 40 to 30 C and the mixture was
left overnight at the same temperature. Then 65 ml of
water was added, precipitate was separated and
aqueous layer was twice extracted with chloroform
40 ml portions. The extract was washed with solution
of sodium carbonate and dried over Na2SO4. Solvent
was evaporated and residue was distilled in a vacuum.
Yield 60%, colorless oil, bp 97 99 C (0.04 mm Hg).
31P NMR spectrum (CDCl3), P, ppm: 18.8, which
corresponds to the compound described earlier [20].
Di[(1R,2S,5R)-( )-menth-2-yl] (S)-hydroxy(iso-
propyl)methylphosphonate (IIf). Prepared similarly
to compound IIa and purified by crystallization from
acetonitrile. Yield 97.6%, mp 71 C, [ ]2D0 82.8
1
(c 2.2, CHCl3). H NMR spectrum (CDCl3), , ppm
(J, Hz): 1.31 br (1H, OH); 4 t (0.3H, CHP, JHH 5.7);
3.43 t (0.7H, CHP, JHH 5.7); 4.09 m (2H, OCH); 31P
NMR spectrum (CDCl3), P, ppm: 24.04; 24.27.
Found, %: P 7.18. C24H47O4P. Calculated, %: P 7.19.
( )-(S)-Phenyl(hydroxymethyl)phosphonic acid
(VIII). a. To a solution of hydroxymethylphosphonate
II (1 g) in 50 ml of dioxane was added 25 ml of 6 N
hydrochloric acid was added. The reaction mixture
was left for 3 days at 80 C. The process of hydrolysis
was monitored by 31P NMR spectroscopy. After com-
pleting the solvent was evaporated, the residue was
dissolved in ethanol and cyclohexylamine excess
( 1.5 ml) was added. The dicyclohexylammonium salt
precipitate was filtered off.
Diethyl (S)-( )-2-hydroxy-3-chloropropylphos-
phonate (VIIb). a. To 0.463 g of sodium borohydride
in 30 ml of THF with stirring was added 1.839 g of
(R,R-(+)-tartaric acids. The mixture was refluxed for
4 h. Then at 30 C to the mixture was added a solu-
tion of 0.7 g of diethyl 2-oxo-3-chloropropylphos-
phonate in 7 ml of THF and after stirring for 24 h
18 ml of ethyl acetate and 20 ml of 1 N HCl was
added. Organic layer was separated and aqueous layer
was extracted with ethyl acetate (3 portions 10 ml).
Combined extracts were dried over anhydrous sodium
sulfate. After evaporation 0.65 g (92%) of colorless
oil was obtained.
b. Sodium iodide (1 equiv.), trimethylchlorosilane
(1 equiv.) and a solution of -hydroxyphosphonate
IIa IIc (1 equiv.) in acetonitrile (10 ml) were mixed.
The reaction mixture was refluxed for 12 h. The pre-
cipitate formed was filtered off, solvent was eva-
porated in a vacuum and a mixture of methylene chlo-
ride (3 ml) and water (2.5 ml) was added. The mixture
was stirred at room temperature for 2 h and then
volatile products were removed in a vacuum. The
residual hydroxyphosphonic acid was dissolved in
ethanol and cyclohexylamine excess was added.
Dropped solid was filtered off and recrystallized. The
compound obtained is ( )-(S)-VIIIb: yield 50%, mp
226 C, [ ]2D0 +14.0 (c 1, MeOH water 1:1) which
corresponds to (S)-configuration of the acid VIII. The
b. To sodium borohydride (1.19 mmol) suspended
in 8 ml of THF (L)-proline (1.19 mmol) was added.
The mixture was stirred at room temperature for 12 h
and then ketophosphonate (0.795 mmol) was added
with stirring. Stir was continued for 24 h, solvent was
evaporated and 10 ml of water ethyl acetate mixture
(1:1) was added to the residue. Organic layer was
separated and water layer was extracted with ethyl
acetate. The extract was washed with 1 N HCl, then
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 7 2006

1030
NESTEROV, KOLODYAZHNYI
with solution of sodium carbonate and again with
water. After evaporation colorless oil was obtained,
4. Kolodiazhnyi, O.I., Advances in Asymmetric Synthesis,
London: JAI Press, 1998, Vol. 3, 1998, pp. 273, 357.
yield 85%, [ ]2D0 12.42 (c 3.22, CHCl3). H NMR
5. Kolodiazhnyi, O.I., Tetrahedron: Asymmetry, 1998,
1
3
spectrum (CD3OD), , ppm (J, Hz): 1.35 t (6H, JHH
vol. 9, no. 8, p. 1279.
3
7.2, CH3CH2); 1.9 d.d.d (1H, 2JHP 18.6, JHH 3.6,
6. Meier, C. and Laux, W.H.G., Tetrahedron: Asym-
metry, 1995, vol. 6, no. 5, p. 1089.
2
3
2JHH 15.3, PCaH); 2.12, d.d.d (1H, JHP 17.4, JHH 9,
2JHH 15.3, PCbH); 3.35, d.d (1H, JHP 11.2, JHH 6.9,
7. Meier, C. and Laux, W.H.G., Tetrahedron, 1996,
vol. 52, no. 2, p. 589.
8. Kitamura, M., Tokunaga, M., Pham, T., Lubell, W.D.,
and Noyori, R., Tetrahedron Lett., 1995, vol. 36,
no. 32, p. 5769.
9. Kolodiazhna, A.O., Kukhar, V.P., Chernega, A.N.,
and Kolodiazhnyi, O.I., Tetrahedron:Asymmetry, 2004,
vol. 15, no. 13, p. 1961.
10. Kolodiazhnyi, O.I. and Guliaiko, I.V., Zh. Obshch.
Khim., 2004, vol. 74, no. 10, p. 1746.
11. Kolodiazhnyi, O.I. and Guliaiko, I.V., Zh. Obshch.
Khim., 2003, vol. 73, no. 11, p. 1926.
12. Nesterov, V.V., Grishkun, E.V., and Kolodyazh-
nyi, O.I., Zh. Obshch. Khim., 2004, vol. 74, no. 12,
p. 2060.
3
2
3
2
4JHH 1, CaHCl); 3.53, d.d.d (1H, JHP 10, JHH 6.3,
4JHH 3.3, CbHCl); 4.05, m (5H, CH2O + CHOH);
4.7 m (1H, OH). 31PNMR spectrum (CDCl3), P, ppm:
29.4. Found, %: P 13.50. C7H16ClO4P. Clculated, %:
P 13.43.
(S)-2-Hydroxy-3-chloropropylphosphonic acid
(IX). A solution of 0.433 g (1.87 mmol) of hydroxy-
phosphonate VIIb in methylene chloride was treated
by 2 ml of trimethylbromosilane and left overnight.
The mixture was then evaporated and 4.5 ml of 60%
aqueous ethanol was added to the residue. Yield
98%, oil. The product was spectroscopically pure
and therefore was used for further reaction without
1
additional purification. H NMR spectrum (CD3OD),
, ppm (J, Hz): 1.6 1.9 m (2H, PCH2); 3.2 3.4 m
(2H, CH2Cl); 4.8 m (1H, CHO); 4.9 br (OH). 31P
NMR spectrum (CD3OD), P, ppm: 25.5.
13. Nesterov, V.V. and Kolodyazhnyi, O.I., Zh. Obshch.
Khim., 2005, vol. 75, no. 7, p. 1225.
14. Seyden-Penne, J., Reduction by the Alumino- and
Borohydrides in Organic Synthesis, New York: Wiley,
1997, p. 6.
15. Kolodiazhnyi, O.I., Tetrahedron, 2003, vol. 59,
no. 32, p. 5923.
16. Blazis, V.J., Koeller, K.J., and Spilling, C.D., J. Org.
Chem., 1995, vol. 60, no. 4. p. 931.
17. Nesterov, V.V. and Kolodiazhnyi, O.I., XIVth Int.
Conf. on Chem. of Phosph. Comp., Kazan, 2005, p. 99.
18. Kielbasinski, P., Luczak, J., and Mikolajczyk, M.,
J. Org. Chem., 2002, vol. 67, no. 22, p. 7872.
19. Wang, K., Zhang, Y. and Yuan, C., Org. Biomol.
Chem., 2003, vol. 1, no. 20, p. 3564.
20. Yuan, C., Wang, K. and Li, Z., Heteroatom. Chem.,
2001, vol. 12, no. 6, p. 551.
21. Wroblewski, A.E. and Halajewska-Wosik, A., Eur. J.
Org. Chem., 2002, no. 16, p. 2758.
(R)-(+)-2-Hydroxy-3-(N,N,N-trimethylammo-
nium)propylphosphonic acids [(R)-(+)-Phospho-
carnitine] (XI). To the acid S-IX (1.88 mmol) 16 ml
of 29% aqueous trimethylamine was added and the
mixture was left for 48 h at 400C. After evaporation
an oil was obtainet in residue which was purified by
column chromatography with silica gel, eluent me-
thanol water. Colorless crystalline compound was
obtained. Yield 80%, mp above 2500C (decomp.),
[ ]2D0 +17.85 (c 1.26, H2O). 1H NMR spectrum
3
(CD3OD), , ppm (J, Hz): 1.80 d.d.d (1H, JHH 6.6,
2
3
2JHH 14.7, JHP 18, PCaH); 1.89 d.d.d (1H, JHH 6.9,
2
2JHH 14.8, JHP 17.7, PCbH); 3.2 s (9H, CH3N); 3.4
d.d (2JHH 13.8, JHH 9.8, CHaN); 3.6 d.d (2JHH 13.8,
3
3JHH 1.2, CHbN); 4.5 m (1H, CHOH); 4.9 5.0 br (1H,
OH). 31P NMR spectrum (CD3OD), P, ppm: 18.7.
Found, %: P 15.62. C5H16NO4P. Calculated, %:
P 15.63.
22. Yokomatsu, T., Yamagishi, T. and Shibuya, S., Tetra-
hedron: Asymmetry, 1993, vol. 4, no. 8, p. 1779.
23. Zymanczyk-Duda, E., Lejczak B., Kafarski, P.,
Grimaud, J., and Fischer, P., Tetrahedron, 1995,
vol. 51, no. 49, p. 11809.
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24. Burkert, U. and Allinger, N.L., Molecular Mechanics,
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2. Kolodiazhnyi, O.I., Tetrahedron: Asymmetry, 2005,
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