Enantioselective reduction of 2-keto-3-haloalkane phosphonates by Baker's yeast

Article abstract of DOI:10.1002/hc.1084

Bioreduction of 3-substituted-2-oxoalkanephosphonates by baker's yeast afforded 3-substituted-2-hydroxy-alkanephosphonates in moderate to good yields and ee value. These compounds could serve as useful chirons for the stereoselective synthesis of phosphorus analogs of biologically active molecules including R-(-)-3-trimethylammonium-2-hydroxypropanoic acid and R-(-)-3-trimethylammonium-2-hydroxypropanoic acid.

Full text of DOI:10.1002/hc.1084

Heteroatom Chemistry
Volume 12, Number 6, 2001
Enantioselective Reduction
of 2-Keto-3-Haloalkane Phosphonates
by Baker’s Yeast
Cheng-ye Yuan, Ke Wang, and Zu-yi Li
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China;
Fax: +86-21-64166128; E-mail: yuancy@pub.sioc.ac.cn
Received 1 March 2001; revised 4 April 2001
As important illustrative examples, (R)-( )-3-amino-
ABSTRACT: Bioreduction of 3-substituted-2-oxoal-
2-hydroxybutyric acid (GABOB) and (R)-( )-3-
kanephosphonates by baker’s yeast afforded 3-substi-
trimethylammonium-2-hydroxypropanoic acid [(R)-
tuted-2-hydroxy-alkanephosphonates in moderate to
( )-Carnitine] can be cited, since the former has
good yields and ee value. These compounds could
been used as an antiepileptic and hypotensive drug,
serve as useful chirons for the stereoselective synth-
while the latter is a vitamin-like compound that is
esis of phosphorus analogs of biologically active
responsible for the metabolism of long-chain fatty
molecules including R-( )-3-trimethylammonium-
acids by regulating their transport through mito-
2-hydroxypropanoic acid and R-( )-3-trimethylam-
chondrial membranes. It is most important to note
C
monium-2-hydroxypropanoic acid. 2001 John Wiley
& Sons, Inc. Heteroatom Chem 12:551–556, 2001
that the corresponding (S)-enantiomer of Carnitine
acts as a competitive inhibitor of carnitine acyltrans-
ferase, causing depletion of the (R)-Carnitine level
in heart tissue. Consequently, synthetic study of the
INTRODUCTION
phosphorus analogs of GABOB and Carnitine, par-
ticularly their stereoisomers, aroused our interest.
In this article, a stereoselective synthesis of 3-halo
(or azido)-2-hydroxypropanephosphonates by biore-
duction with baker’s yeast is discussed. In addition
to phosphorus analogues, the target molecules can
be regarded as useful phosphonate chirons for the
preparation of optically active polyfunctional phos-
phonates with biological significance.
Baker’s yeast (Saccharomyces cerevisiae) is now well
recognized as a valuable stereoselective reagent in
biotransformations of organic compounds [1–3].
The asymmetric reduction of carbonyl groups with
this microbiological substance has been studied ex-
tensively, but little is known about its activity toward
ketophosphonates [4]. On the other hand, chiral
-
hydroxyalkanephosphonic acids have received much
attention because of their unique physiological activ-
ities as well as their ability to mimic the correspond-
ing hydroxy- or amino-alkanecarboxylic acids [5].
RESULTS AND DISCUSSION
The 3-halo-2-oxopropanephosphonates 1a–g were
prepared according to the literature [6], while the
corresponding azido derivative 1h was obtained
by reaction of 1e with sodium azide in DMF. We
found that 3-iodo-2-oxopropanephosphonates were
not suitable substrates in this case due to their
instability.
Studies on organophosphorus compounds 110.
Correspondence to: Chengye Yuan.
Contract Grant Sponsor: Nationial Natural Science Foundation
of China (NNSFC).
Contract Grants Number: 20072052 and 29832050.
2001 John Wiley & Sons, Inc.
c
551

552 Yuan, Wang, and Li
O
P
O
P
moiety is the smaller one. Furthermore, under the
same conditions, stereoselectivity of the reduction
is strongly dependent on the chemical struc-
ture of 3-substituted 2-oxopropanephosphonates.
As shown in Table 1, the ee values of the 3-
bromo-2-hydroxypropanephosphonates are much
larger than those of the corresponding chloro-
counterparts (e,f,g vs. b,c,d). The ee value of 3-
azido-2-hydroxypropanephosphonate 2h was found
to be up to 92%. These data demonstrated that the
electron-withdrawing ability of the substituent on
position 3 plays the dominating factor in governing
the magnitude of the ee value of these reaction sys-
tems. Furthermore, the ee value of this bioreduction
is also influenced significantly by the steric effect.
Data in Table 1 show that the diisopropyl 3-halo-2-
keto-propanephosphonates 1e and f gave only 13 and
52% ee values, respectively. It seems that the keto-
phosphonates with bulky diisopropyl groups hin-
dered the bioreduction process.
For the purpose of improving the enantio-
selectivity of the reduction, we introduced several
experimental modifications. Either by adding dehy-
drogenase inhibitors, such as allyl alcohol, methyl
vinylketone, and L-cysteine, or by the variation of ra-
tio between the substrates 1a–g and cosolvents, how-
ever, no significant improvement was observed; trials
on the increase of the enatioselectivity of the micro-
bial reduction are being carried on in our laboratory.
The unexpected experimental data in Table 1,
that is, the low yield of bioreduction of 1e, f,
and g, attracted our attention. By careful study
of the reaction products, in addition to 3-bromo-
2-hydroxypropanephosphonates 2e,f, and g, a signi-
ficant amount (30–35%) of 2-keto-propanephosph-
onates 3e,f, and g were isolated as by-products of
the reaction (Scheme 2).
O
OH
*
O
RO
RO
RO
RO
RO
v
i, ii, iii
P
Me
X
X
RO
1a-g
2a-h
1e
1h
iv
SCHEME 1 Reagents and conditions: (i) n-C4H9Li; (ii) CuCl
or CuBr; (iii) ClCOCH2Cl or BrCOCH2Br; (iv) NaN3/DMF, 0 C;
(v) baker’s yeast, 30 C
The substrates 1a–h thus obtained are stable in
aqueous medium and undergo bioreduction with
baker’s yeast as illustrated in Scheme 1. The bio-
transformation was performed by shaking an aque-
ous (50 mL) suspension of dried baker’s yeast (5 g)
and substrate (0.5 mmol) at 30 C until the disappear-
ance of the substrate was observed, as monitored by
thin-layer chromatography (TLC).
As shown in Table 1, all 2-keto-3-halo/azido
propanephosphonates (1a–h) can be transformed
conveniently into the corresponding 2-hydroxypro-
panephosphonates (2a–h) in moderate to good yields
and enantiomeric excess (ee) value. The enatioselec-
tivity of the reaction was determined by means of 31
P
NMR spectroscopy using quinine as a chiral discim-
inating agent, and this method may be applied for
the tentative estimation of their configuration [7, 8].
In the meantime, the absolute configurations of the
3-substituted-2-hydroxypropanephosphonates were
preliminarily assigned on the basis of two features:
(1) the measurement of 1 values in 1H NMR
spectra of their -methoxy- -trifluoromethylphenyl
acetic acid (MTPA) esters using the modified
Mosher’s method [9], and (2) according to the
general experimental observation, bioreduction of
ketones by baker’s yeast usually obeys Prelog’s
rule [10]. In our case, the phosphonate group
is the larger substituent, while the chloromethyl
However, no dechlorinated products could
be detected from the corresponding 3-chloro-2-
oxopropanephosphonates. On the other hand, as
found by Hamdani et al. [11], a free-radical reductive
dehalogentation had taken place in the treatment of
ethyl 2-chloro-3-oxobutanoate with baker’s yeast in
aqueous medium. Such an explanation is not ap-
plicable to our case, due to the different chemical
environment of the halogen atom in the molecule.
Consequently, the reaction mechanism for the
TABLE 1 Reduction of 1a–e with Baker’s Yeast
Substrate
R
X
Time (h) Yield (%) ee (%)a Configb
1a
1b
1c
1d
1e
1f
Me Cl
Et Cl
iPr Cl
nBu Cl
24
12
24
24
24
24
24
12
74
82
57
70
72
13
70
83
52
87
92
R
R
—
R
R
—
R
88
Et
Br
35c
41c
55c
77
iPr Br
nBu Br
Ets N3
1g
1h
S
aThe ee(%) was determined by the use of quinine as a chiral solvating
agent [7, 8].
b The absolute configuration was determined according to Mosher’s
methods [9].
c The 2-oxopropanephosphonate was isolated as a by-product.
SCHEME 2

Enantioselective Reduction of 2-Keto-3-Haloalkane Phosphonates by Baker’s Yeast 553
structure of the 3-substituted-alkanephosphonate
chirons for the stereospecific synthesis of polyfunc-
tional phosphonates, which display promising or po-
tential biological activities.
O
O
P
OH
O
K2CO3,THF EtO
EtO
EtO
P
Cl
EtO
reflux
4
2b
SCHEME 3
EXPERIMENTAL
IR spectra were recorded on a Shimadzu IR-440
O
OH
O
OH
spectrometer. EI-MS were run on an Hp-5989A mass
H2/Pd-C
EtO
EtO
EtO
spectrometer. 1H and 13P NMR spectra were recorded
P
NH2
P
N3
EtO
on a Bruker AMX-330 (300 MHz) spectrometer in
5
CDCl3 solutions, and chemical shifts ( ) were re-
ported in ppm downfield relative to TMS (internal
standard) and 80% phosphoric acid (external stan-
dard) in phosphorus spectra.
2h
SCHEME 4
Baker’s yeast was purchased from Sigma Co. Int.
Spots in TLC monitoring were visualized by dip-
ping the plate into a solution of 24 g of (NH4)6Mo7
O24 4H2O and 1 g of Ce(SO4)2 4H2O in 500 mL of 10%
H2SO4 in water, followed by heating with a hot gun.
formation of debrominated compounds (3e,f,g) is
not yet clear. It should be pointed out that when
3e, 3f, and 3g were treated with baker’s yeast, even
for several days, no 31P NMR signal for 2-hydroxy-
propanephosphonate was detected, even when the
starting substrates had completely disappeared, as
monitored by TLC. It is reasonable to conclude that
3-halo-2-oxo propanphosphonates undergo reduc-
tion mediated by baker’s yeast much faster than does
2-oxopropanephosphonates.
As shown by our scaled-up experiments,
10 mmol of compounds 1a, 1b, 1d, and 1h can effi-
ciently be reduced to the corresponding hydroxypro-
panephosphonates with 25 g baker’s yeast without
the loss of yield and optical purity of the products.
Consequently, the bioreduction method described by
us has potential application for large-scale prepara-
tions.
3-Substituted-2-oxopropanephosphonates (1)
Under a nitrogen atmosphere, butyllithium (0.05
mol) was added at 78 C to tetrahydrofuran (30 mL),
followed by addition of the dialkylalkanephospho-
nate (0.05 mol), after 30 minutes of stirring, CuCl(or
CuBr) (0.05 mol) was added, and the reaction mix-
ture allowed to warm to 30 C during an hour. The
acyl chloride (0.055 mol) in ether (50 mL) was added,
and the mixture was allowed to warm to room tem-
perature. Water (50 mL) was added, and the solution
was filtered and washed with dichloromethane. The
combined organic layers were dried with MgSO4,
and the product was purified by column chromatog-
raphy (hexane/acetone as eluent, v/v = 2/1).
3-Halo-2-hydroxypropanephosphonates
2a–g
could readily be converted to 2,3-epoxypropanephos-
phonates in the presence of potassium carbonate;
for example, diethyl 2,3-epoxypropanephosphonate
(4) was prepared from diethyl 3-chloro-2-hydroxy-
propanephosphonate (2b) (Scheme 3). The ena-
tionmetric 2,3-epoxypropane phosphonates thus
obtained are useful three-carbon phosphonate
chirons for the synthesis of Fosfomycin derivatives
[12,13,14].
Diethyl 3-azido-2-hydroxypropanephosphonate
(2h), on hydrogenation using palladium on carbon
as catalyst, provided diethyl 3-amino-2-hydroxypro-
pane phosphonate (5), which is the phosphorus ana-
log of (R)-GABOB (Scheme 4).
Dimethy3-chloro-2-oxopropanephosphonate(1a).
Colorless oil; Rf = 0.30; 7.30 g (yield 73%); IR ( ):
1
2980, 1735 (C O), 1250, 1028 cm , 1H NMR
( ): 4.37(s, 2H, CH2Cl), 3.88 (d, 6H, J = 11 Hz,
POMe), 3.37 (d, 2H, J = 23 Hz, PCH2). MS (m/e, %):
201(M + 1), 183, 151(base), 109, 79. Anal Calcd for
C5H10ClO4P: C, 29.94; H, 5.03; P, 15.44. Found: C,
29.90; H, 5.08; P, 15.13.
Diethyl 3-chloro-2-oxoproanephosphonate (1b).
Colorless oil; Rf = 0.45; 6.31 g (yield 55%); IR( ):
Therefore, reduction of 3-substituted-2-oxoal-
kanephosphonates by baker’s yeast afforded the cor-
responding hydroxyalkanephosphonates in moder-
ate to good yields and ee values. Stereoseletivity of
the reduction was heavily dependent on the chemical
1
2985, 1736 (C O), 1396, 1252, 1025 cm ,1H NMR
( ): 4.25(s, 2H, CH2Cl), 4.15 (m, 4H, PCH2CH3), 3.28
(d, 2H, J = 22 Hz, PCH2), 1.32 (m, 6H, PCH2CH3). MS
(m/e, %): 229 (M + 1), 179, 151, 137, 109, 81. Anal.

554 Yuan, Wang, and Li
Calcd for C7H14ClO4P (228.61): C, 36.78; H, 6.17; P
13.55. Found: C, 36.81; H, 6.20; P, 13.49.
oxoproanephosphonate (1e) (0.273 g, 1.1 mmol)
in DMF (10 mL) was added NaN3 (0.071 g) at 0 C,
and the resulting mixture was stirred while being
monitored by TLC. After 4–6 hours, water (50
mL) was added, and the solution was washed with
dichloromethane (20 mL 4). The product was pu-
rified by column chromatography (hexane/acetone
= 2/1).
Diisopropyl
3-chloro-2-oxoproanephosphonate
(1c). Colorless oil; Rf = 0.50; 9.73 g (yield 76%);
1
1
IR( ): 2984, 1736 (C O), 1388, 1252, 992 cm , H
NMR ( ): 4.70 (m, 2H, P(O)OCH(CH3)2), 4.26 (s,
2H, CH2Cl), 3.16 (d, J = 21 Hz, PCH2), 1.32 (12H,
d, POCH (CH3)2). MS (m/e, %): 257 (M + 1), 215,
165, 123, 43. Anal. Calcd for C9H18ClO4P (256.66):
C, 42.12; H, 7.07. Found: C, 42.23; H, 7.14.
Colorless oil; R = 0.55; yield 85%; IR( ): 2987,
f
1
2913, 2109(s), 1730(C O), 1256, 1025 cm . 1H
NMR ( ): 4.15(m, 6H, POCH2CH3 + CH2N3), 3.10
(d, 2H, J = 19 Hz, PCH2), 1.35 (m, 6H, POCH2CH3).
MS (m/e, %): 236 (M + 1), 208, 179, 151, 123, 109,
81. Anal Calcd for C7H14N3O4P (235.18): C, 35.75; H,
6.00; N, 17.54. Found: C, 35.93; H, 6.10; N, 17.62.
Dibutyl 3-chloro-2-oxoproanephosphonate (1d).
Colorless oil; Rf = 0.65; 7.67 g (yield 54%); IR( ):
1
1
2963, 1737(C O), 1256, 1026 cm . H NMR ( ):
4.35 (s, 2H, CH2Cl),4.15 (m, 4H, POCH2C3H7), 3.31
(d, 2H, J = 22 Hz, PCH2), 1.70 (m, 4H, POCH2
CH2CH2CH3), 1.45(m, 4H, POCH2CH2 CH2CH3), 0.97
(m, 6H, POCH2 CH2CH2CH3). MS (m/e, %): 285
(M + 1), 229, 173,123 (base), 105, 57. Anal Calcd for
C11H22 ClO4P (284.72): C, 46.40; H, 7.79; P, 10.88.
Found: C, 46.62; H, 7.56; P, 10.78.
General Procedure for the Reaction of Baker’s
Yeast with 1a–1h
Baker’s yeast (5 g) was suspended in water (50 mL),
then each phosphonate 1a–h (0.5 mmol) was added
and the mixture was shaken at 30 C, while being
monitored by TLC. The biomass was removed and
extracted with ethyl ether and with chloroform (20
mL 3). The combined organic layers were dried over
anhydrous MgSO4, and the solvents were removed
under reduced pressure. The product was separated
by column chromatography(hexane/acetone = 3/2).
Diethyl 3-bromo-2-oxoproanephosphonate (1e).
Colorless oil; Rf = 0.46; 8.19 g (yield 60%); IR( ):
1
1
2986, 1733(C O), 1394, 1253, 1025 cm . H NMR
( ): 4.15 (m, 6H, POCH2CH3 + CH2Br), 3.35 (d,
2H, J = 23 Hz, PCH2), 1.40 (6H, POCH2CH3). MS
(m/e, %): 274 (M + 1), 193, 179 (base), 165,
123, 109. Anal Calcd for C7H14BrO4P (273.06): C,
30.79; H, 5.17; P, 11.34. Found: C, 30.94; H, 5.15;
P, 11.04.
Conversion of 3-Substituted-2-hydroxyproane-
phosphonates (2) to the Corresponding
-Methoxy- -trifluoromethylphenyl-
Acetic Acid (MT-PA) Esters
Diisopropyl 3-bromo-2-oxoproanephosphonate
(1f). Colorless oil; Rf = 0.55; 6.77 g (yield 45%);
To a stirred solution of 0.1 mmol (R)[or (S)]- -me-
thoxy- -trifluoromethylphenyl acetic acid (MTPA)
in 1 mL anhydrous CH2Cl2 was added 0.1 mmol
of hydroxypropanephosphonates (2) and 2–3 mg
of DMAP. The dicyclohexlcarbodiimide (DCC) (0.1
mmol) was added to the reaction mixture at 0 C,
which was then stirred for 8 hours at 0 C. Precipi-
tated urea was then filtered off. CH2Cl2 (20 mL) was
added, and the solution was washed twice with satu-
rated NaHCO3 solution and then dried with MgSO4.
The solvent was removed by evaporation, and the
ester was purified by column chromatography (hex-
ane/acetone = 3/2).
1
IR( ): 2987, 1773(C O), 1280, 1254 cm . 1H
NMR ( ): 4.76(m, 2H, POCH(CH3)2),4.34 (s, 2H,
CH2Br), 3.23(d, 2H, J = 23 Hz, PCH2), 1.36 (12H, d,
POCH(CH3)2). MS (m/e, %): 302 (M + 1),165. Anal
Calcd for C9H18BrO4P (301.12): C, 35.90; H, 6.03.
Found: C, 35.97; H, 6.15.
Dibutyl 3-bromo-2-oxoproanephosphonate (1g).
Yellow oil; Rf = 0.65; 9.04 g (yield 55%); IR( ): 2963,
1
1
1734(C O), 1255, 1025 cm . H NMR ( ): 4.07(s,
2H, CH2Br), 4.02 (m, 4H, POCH2), 3.27 (d, 2H, J
= 22 Hz, PCH2), 1.62 (4H, m, POCH2CH2CH2CH3),
1.35 (4H, m, POCH2CH2CH2CH3), 0.89 (6H, m,
POCH2CH2CH2 CH3). 31P NMR ( ): 19.8. MS (m/e,
%): 331 (M + 2), 329, 275, 273, 137, 123 (base), 57,
41. Anal Calcd for C11H22BrO4P (329.17): C, 40.13; H,
6.74. Found: C, 40.34; H, 6.77.
(R)-Dimethyl 3-chloro-2-hydroxypropanephosph-
onate (2a). Colorless oil; Rf = 0.35; 74 mg (yield =
1
74%), ee 72%; IR( ): 3340(OH), 1228(P O) cm .
1H NMR ( ): 4.25(1H, -OH); 3.80 (d, 6H, 2CH3OP);
3.55 (d, 2H, CH2Cl); 3.50 (m,CHOH); 2.10 (m, 2H,
CH2P); 31P NMR ( ): 31.8; MS (m/e, %): 203 (M + 1,
base), 185, 153, 109, 79; Anal. Calcd for C5H12ClO4P
Diethyl 3-azido-2-oxo-proanephosphonate (1h).
To
a
stirred solution of diethyl 3-bromo-2-

Enantioselective Reduction of 2-Keto-3-Haloalkane Phosphonates by Baker’s Yeast 555
(202.57): C, 29.63; H, 5.93; P, 15.29. Found: C, 29.39;
H, 5.79; P, 15.18.
(R)-Diethyl 3-bromo- 2-hydroxypropanephospho-
nate (2e). Colorless oil; Rf = 0.50; 48 mg (yield 35%),
ee 83%; IR( ): 3339 (-OH), 1226 (P O), 1055 (P-
1
OC2H5) cm , 1H NMR ( ): 4.15 (m, 4H, OCH2CH3),
(R)-Diethyl 3-chloro-2-hydroxypropanephosphon-
3.52 (d, 2H, CH2Br), 3.10 (1H, OH), 2.10 (m, 2H,
CH2P), 1.36 (m, 6H, OCH2CH3). 31PNMR ( ): 29.2.
MS (m/e, %):277 (M + 2, base), 275, 259, 181, 125,
107; Anal. Calcd for C7H16BrO4P (275.08): C, 30.54;
H, 5.82; Found: C, 30.60; H, 5.91.
ate (2b). Colorless oil; Rf = 0.50; 94 mg (yield 82%),
1
1
ee 70%; IR( ): 3337, 2962, 1222 (P O) cm . H
NMR ( ): 4.35(1H, -OH); 4.10 (m, 4H, OCH2CH3);
3.65 (d, 2H, CH2Cl); 3.30 (m, 1H, CHOH); 2.10 (m,
2H, CH2P); 1.65 (m, 2H, CH2); 1.40 (m, 2H, CH2);
0.95 (m, 6H, CH3CH2O–P); 31P NMR ( ): 28.9 ppm;
MS (m/e, %): 231(M + 1), 181, 153, 125 (base),
107, 81; Anal. Calcd for C7H16ClO4P (230.60): C,
36.52; H, 6.96; P, 13.43; Found: C, 36.56; H, 7.16;
P, 12.95.
1
(R)-MTPA-(R)-(2e): H NMR ( ): 7.56 (2H, Ph),
7.42 (3H, Ph), 5.49 (1H, HCO), 4.12 (m, 4H, POCH2),
3.73(m, CH2Br), 3.64 (s, 3H, OCH3), 2.25 (m, 2H,
PCH2), 1.30 (m, 6H, POCH2CH3).
1
(S)-MTPA-(S)-(2e): H NMR ( ): 7.56 (2H, Ph),
7.42 (3H, Ph), 5.49 (1H, HCO), 4.12 (m, 4H, POCH2),
3.68(m, CH2Br), 3.64 (s, 3H, OCH3), 2.34 (m, 2H,
PCH2), 1.30 (m, 6H, POCH2CH3).
1
(R)-MTPA-(R)-(2b): H NMR ( ): 7.55 (2H, Ph),
7.42 (3H, Ph), 5.52 (1H, HCO), 4.13 (m, 4H, POCH2),
3.87 (m, 2H, CH2Cl), 3.56 (s, 3H, OCH3), 2.21 (m, 2H,
PCH2), 1.31 (m, 6H, POCH2CH3).
1
(S)-MTPA-(R)-(2b): HNMR ( ): 7.55 (2H, Ph),
Diisopropyl 3-bromo-2-hydroxypropane-
phosphonate(2f)
7.42 (3H, Ph), 5.52 (1H, HCO), 4.13 (m, 4H, POCH2),
3.82 (m, 2H, CH2Cl), 3.56 (s, 3H, OCH3), 2.28 (m, 2H,
PCH2), 1.31 (m, 6H, POCH2CH3).
Colorless oil; Rf = 0.55; 62 mg (yield 41%), ee 52%;
1
IR( ): 3300 (-OH), 1375, 1380, 1233 (P O) cm .
1H NMR ( ): 4.78 (2H, POCH(CH3)2), 4.18 (1H, m,
CH1OH), 3.55 (d, 2H, CH2Br), 1.62 (m, 2H, PCH2),
1.33 (12H, d, POCH (CH3)2). 31P NMR ( ): 29.0 ppm.
MS (m/e, %): 302 (M + 1), 221, 219, 201, 203, 167,
139, 125 (base), 43. Calcd for C9H20BrO4P (303.12):
C, 35.66; H, 6.65. Found: C, 35.79; H, 6.55.
Diisopropyl 3-chloro-2-hydroxypropanephospho-
nate (2c). Colorless oil; Rf = 0.55; 73 mg(yield
57%), ee 13%; IR( ):3285(-OH), 2983, 1387, 1377,
1216 (P O), 1021 cm , H NMR ( ): 4.72(m, 2H,
POCH(CH3)2), 4.24(1H, -OH); 3.61 (d, 2H, CH2Cl),
2.05 (m, 2H, CH2P), 1.34(d, 12H, POCH(CH3)2); 31P
NMR ( ): 29.2, MS (m/e, %): 259(M + 1, base),
217, 175, 139, 125, 43; Anal. Calcd for C9H20ClO4P
(258.68): C, 41.70; H, 7.73; P, 11.97; Found: C, 41.70;
H, 7.81; P, 11.79.
1
1
(R)-Dibutyl 3-bromo-2-hydroxypropane-
phosphonate (2g)
Colorless oil; Rf = 0.60; 78 mg (yield 55%), ee 87%;
1
1
IR(cm ): 3337(-OH), 2962, 1222 (P O); H NMR
( ): 4.11 (1H, -OH); 4.07 (m, 4H, POCH2C3H7); 3.51
(d, 2H, CH2Br); 2.20 (m, 2H, CH2P); 1.67 (m, 2H,
CH2); 1.39 (m, 2H, CH2); 0.94 (m, 6H, CH3) ppm.
31P NMR ( ): 29.0. MS (m/e, %): 333 (M + 2), 331,
251, 221, 219, 125 (base), 97; Anal Calcd for C11H24
BrO4P (331.18): C, 39.89; H, 7.30. Found: C, 40.04;
H, 7.47.
(R)-Dibutyl 3-chloro-2-hydroxypropanephospho-
nate (2d) . Colorless oil; Rf = 0.58; 118 mg (yield
88%), ee 70%; IR( ):3337(-OH), 2962, 1222 (P O)
1
cm . 1H NMR ( ): 4.35 (1H, -OH), 4.10 (m, 4H,
OCH2C3H7), 3.65 (d, 2H, CH2Cl), 3.30 (m, 1H, CH),
2.10 (m, 2H, CH2P), 1.65 (m, 2H, CH2), 1.40 (m, 2H,
CH2), 0.95 (m, 6H, CH3). 31P NMR ( ): 28.5. MS (m/e,
%): 287 (m + 1), 237, 175, 157, 125 (base), 107. Anal.
Calcd for C11H24ClO4P (286.73): C, 46.03; H, 8.37; P,
10.80; Found: C, 45.67; H, 8.46; P, 10.97.
(R)-MTPA-(R)-(2d): 7.59 (2H, Ph), 7.47 (3H, Ph),
5.38 (1H, HCO), 4.10 (m, 4H, OCH2C3H7); 3.65 (d,
2H, CH2Cl); 3.64 (s, 3H, OCH3), 2.10 (m, 2H,CH2P);
1.65 (m, 2H, CH2); 1.40 (m, 2H, CH2); 0.95 (m, 6H,
CH3).
(S)-MTPA-(R)-(2d): 7.59 (2H, Ph), 7.47 (3H, Ph),
5.38 (1H, HCO), 4.10 (m, 4H, OCH2C3H7); 3.60 (d,
2H, CH2Cl); 3.64 (s, 3H, OCH3), 2.17 (m, 2H,CH2P);
1.65 (m, 2H, CH2); 1.40 (m, 2H, CH2); 0.95 (m, 6H,
CH3).
(S)-Diethyl 3-azido-2-hydroxypropane-
phosphonate (2h)
Colorless oil; Rf = 0.60; 90 mg (yield 77%), ee 92%;
IR( ): 3343(-OH), 2986, 2105(vs), 1225 (P O), 1050
1
1
(P-OC2H3) cm . H NMR ( ): 4.20(1H, OH), 4.13
(m, 6H, OCH2CH3), 3.37 (d, 2H, CH2N3), 2.01(m,
2H, CH2P), 1.35 (m, 6H, OCH2CH3). 31P NMR ( ):
29.1. MS (m/e, %): 238 (M, base), 181, 153, 125,
107, 72; Anal. Calcd for C7H16N3O4P (238.17): C,
35.30; H, 6.35; N, 17.64; Found: C, 35.22; H, 6.75; N,
17.29.

556 Yuan, Wang, and Li
1
Anal Calcd for C7H15O4P (194.17): C, 43.30; H, 7.78;
Found: C, 43.28; H, 7.75.
(R)-MTPA-(S)-(2h): H NMR ( ): 7.54 (2H, Ph),
7.41 (3H, Ph), 5.39 (m, 1H, HCO), 4.10 (m, 4H,
POCH2), 3.72 (m, 2H, CH2N3), 3.57 (s, 3H, OCH3),
2.16 (m, 2H, CH2P), 1.32(m, 6H, POCH2CH3).
Conversion of (S)-Diethyl-3-azido-2-hydroxypro-
panephosphonate (2h) to (S)-diethyl-3-amino-2-
hydroxypropanephosphonate (5)
1
(S)-MTPA-(S)-(2h): H NMR ( ): 7.54 (2H, Ph),
7.41 (3H, Ph), 5.39 (m, 1H, HCO), 4.13 (m, 4H,
POCH2), 3.62 (m, 2H, CH2N3), 3.57 (s, 3H, OCH3),
2.23 (m, 2H, CH2P), 1.34(m, 6H, POCH2CH3).
The mixture of (S)-diethyl 3-azido-2-hydroxypropa-
nephosphonate (2h) (200 mg) and palladium (10%)
on carbon (10 mg in 20 mL MeOH) was stirred
for 4 hours under hydrogen gas at 25 C. The mix-
ture was filtered, and the solvents were removed
under reduced pressure. The product was purified
to afford 167 mg of (S)-diethyl 3-amino-2- hydrox-
ypropanephosphonate (5), yield 95%.
Diethyl 2-oxopropanephonate (3e). Colorless
1
oil; Rf = 0.25; yield 35%; H NMR ( ): 4.07 (m, 4H,
POCH2CH3), 3.20 (d, 2H, J = 22 Hz, PCH2), 2.30 (s,
3H, COCH3), 1.30 (m, 6H, POCH2CH3). MS (m/e, %):
195 (M + 1), 179, 167, 152, 125, 97, 81.
1H NMR ( ):4.70 (3H, NH2 + OH), 4.05 (m,
4H, POCH2CH3), 2.75 (d, 2H, CH2NH2), 1.30 (m,
2H, POCH2), 1.28 (m, 6H, POCH2CH3). MS (m/e,
%):212 (M + 1), 181, 138, 125, 96, 70; Anal Calcd
for C7H18NO4P (211.20): C, 39.80; H, 8.59; Found: C,
39.56; H, 8.50.
Diisopropyl 2-oxopropanephonate (3f). Color-
1
less oil; Rf = 0.45; yield 35%; H NMR ( ): 4.72 (m,
2H, POCH(CH3)2), 3.09 (d, 2H, PCH2), 2.32(s, 3H,
COCH3), 1.33 (d, 12H, POCH(CH3)2). MS (m/e, %):
223 (M + 1), 180,153,125,97.
Dibutyl 2-oxopropanephonate (3g). Colorless
1
oil; Rf = 0.40; yield 30%; H NMR ( ): 4.05(m, 4H,
REFERENCES
POCH2), 3.16(d, 2H, JPH = 23 Hz, PCH2), 2.32 (s, 3H,
COCH3),1.66 (4H, POCH2CH2CH2CH3), 1.40 (m, 4H,
POCH2CH2CH2CH3), 0.93 (6H, POCH2CH2CH2CH3).
MS (m/e, %): 251 (M + 1), 153, 139, 125, 97, 58.
[1] Csuk, R.; Glanzer, B. I. Chem Rev 1991, 91, 49.
[2] Csuk, R.; Glanzer, B. I. In Stereoselective Biocatalysis;
Patel, R. N., Ed.; Marcel Dekker Inc: New York, 2000;
p. 527.
[3] Servi, S. Synthesis 1990, 8, 1.
[4] Zymanczyk-Duda, E.; Lejczak, B.; Kafarski, P.;
Grimaud, J.; Fischer, P. Tetrahedron 1995, 51, 11809.
[5] Kitamura, M.; Tokunaga, M.; Noyori, R. J Am Chem
Soc 1995, 117, 2931.
Conversion of (R)-Diethyl-3-chloro-
2-hydroxypropanephosphonate (2b) to
(S)-Diethyloxiranylmethylphosphonate (4)
[6] Mathey, F.; Savignac, P. Tetrahedron 1978, 34, 649.
[7] Zymanczyk-Duda, E.; Skwarczynski, M.; Lejczak, B.;
Kafarski, P. Tetrahedron: Asymmetry 1996, 7, 1277.
[8] Skwarczynski, M.; Lejczak, B.; Kafarski, P. Chirality
1999, 11, 109.
[9] Dale, J. A.; Dull, D. L.; Mosher, H. S. J Org Chem 1969,
34, 2543.
[10] Prelog, V. Pure Appl Chem 1964, 9, 179.
[11] Hamdani, M.; De Jeso, B.; Deleuze, H.; Saux, A.;
Maillard, B. Tetrahedron: Asymmetry 1993, 4, 1233.
[12] Carbon, O.; Buisson, D.; Larcheveque, M.; Azerad, R.
Tetrahedron: Asymmetry 1995, 6, 2199.
[13] Tadeusiak, E.; Krawiecka, B.; Michalski, J. Tetrahe-
dron Lett 1999, 40, 1791.
To a stirred solution of compound (R)-diethyl-3-
chloro-2-hydroxypropane phosphonate 2b (0.228 g,1
mmol) in tetrahydrofuran (20 mL), K2CO3 (0.138 g,
2 mmol) was added at room temperature, the result-
ing mixture was refluxed while monitored by TLC,
and the product was purified by column chromatog-
raphy (hexane/acetone, v/v = 3/2) to afford 0.178 g of
(S)-diethyl oxiranylmethyl phosphonate (4).
Colorless oil; Rf = 0.33,yield 92%. IR( ): 1250
1
(P O),1158 (P-OC2H5), 1020 cm . 1H NMR ( ): 4.05
(m, 4H, POCH2CH3), 3.20 (m, 1H, CHO), 2.55 (m,
2H,CH2O), 1.83 (m, PCH2), 1.28 (m, 6H, POCH2CH3).
MS (m/e, %): 195(M + 1), 167, 149, 139, 121, 109, 81.
[14] Wroblewski, A. E.; Halajewska-Wosik, A. Tetrahe-
dron: Asymmetry 2000, 11, 2053.