Enzymatic synthesis of optically active δ-hydroxy-β-ketoalkanephosphonates

Article abstract of DOI:10.1016/S0957-4166(02)00761-9

A novel and enantioselective approach to δ-hydroxy-β-ketoalkanephosphonates has been developed via CALB-catalyzed enantioselective acetylation and CRL-catalyzed enantioselective hydrolysis.

Full text of DOI:10.1016/S0957-4166(02)00761-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 63–70
Enzymatic synthesis of optically active
d-hydroxy-b-ketoalkanephosphonates†
Yonghui Zhang, Chengfu Xu, Jinfeng Li and Chengye Yuan*
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China
Received 10 August 2002; accepted 31 October 2002
Abstract—A novel and enantioselective approach to d-hydroxy-b-ketoalkanephosphonates has been developed via CALB-cata-
lyzed enantioselective acetylation and CRL-catalyzed enantioselective hydrolysis. © 2003 Elsevier Science Ltd. All rights reserved.
to HWE reaction, would provide the molecules 1 bear-
ing multi functionalities which could find many applica-
tions in synthetic organic chemistry. Additionally,
many natural products such as yashabushiketol were
found to have such a structural unit.6 Herein, we wish
to report a facile enzymatic approach to chiral d-
hydroxy-b-ketoalkanephosphonates and their chemical
conversion to 1 via HWE reactions.
1. Introduction
Undoubtedly, the most common synthetic application
of phosphonates is their use in the Horner–
Wadsworth–Emmons (HWE) reaction for preparing
a,b-unsaturated carbonyl compounds from condensa-
tion of an aldehyde or ketone.1 Synthesis of non-
racemic b-ketophosphonates has aroused great interest
during the past decades since such chirons could lead
directly to chiral enones. The existing practical routes
leading to non-racemic b-ketophosphonates were
mainly focused on the Michaelis–Arbuzov synthesis2
and the acylation of alkylphosphonates.3 Another inter-
esting approach to chiral g-hydroxy-b-ketophospho-
nates was based on Sharpless epoxidation for access to
the aldehyde.4 Our group has also exploited baker’s
yeast-mediated enantioreduction for preparing some
optically active g-hydroxy-b-ketophosphonates and d-
hydroxy-b-ketophosphonates.5 Continuing our studies
on enzymatic reactions of hydroxyalkanephosphonates,
we report the convenient synthesis of optically active
2. Results and discussion
The racemic d-hydroxy-b-ketoalkanephosphonates
could be easily prepared by reacting the carbanion
derived from b-ketopropanephosphonates with an alde-
hyde as previously described.7 It is known that the
utility of lipases for the efficient resolution of alcohols
and related compounds is of great importance in
organic synthesis, and we wish to exploit such hydro-
d-hydroxy-b-ketoalkanephosphonates
antarctica lipase B- and crude Candida rugosa lipase-
catalyzed kinetic resolutions. Those chirons, subjected
via
Candida
Scheme 1.
* Corresponding author. Fax +86-21-64166128; e-mail: yuancy@pub.sioc.ac.cn
† Studies on organophosphorus compounds 124.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00761-9

64
Y. Zhang et al. / Tetrahedron: Asymmetry 14 (2003) 63–70
Scheme 2.
Scheme 3.
lases for the convenient preparation of these interesting
alcohols. C. antarctica lipase B could efficiently resolve
a lot of secondary alcohols bearing a medium sized
group less than the propyl moiety.8 Recently, we
reported C. antarctica lipase B-catalyzed enantioselec-
tive acetylation of hydroxyalkanephosphonates bearing
methyl, ethyl or vinyl group as the medium group
(Scheme 1).9
time and caused racemization under our reaction condi-
tions. Treated with benzaldehyde using K2CO3/H2O
system, 3a–c gave chiral enones 6a–c with 95–99%
enantiomeric excess. It can be inferred that the ee of
3a–c is even higher. As to the acetylated products,
further enzymatic hydrolysis is necessary since chemical
hydrolysis caused unavoidable elimination to olefins.
As this enzymatic process may enhance the enan-
tiomeric excess of the hydrolyzed 5a–c, the ee of their
HWE products 7a–c is excellent as shown in Table 1.
Herein, the scope of this method is extended, which
leads to the formation of chiral d-hydroxy-b-ketobu-
tanephosphonates (Scheme 2).
We have also developed C. rugosa lipase-catalyzed
enantioselective hydrolysis in water-equilibrated diiso-
Under our reaction conditions, the racemic 2a–c, sub-
jected to CALB-catalyzed acetylation in benzene, pro-
vided unreacted 3a–c in 35–42% yield and acetylated
products 4a–c in 48–51% yield. Unfortunately, the
enantiomeric excess of the unreacted alcohols 3a–c
could not be determined by chiral HPLC after many
trials. Mosher’s method (especially 3c) is not applicable
here due to the elimination to olefin by a base in the
course of synthesis, which may cause partial racemiza-
tion. We try to convert those racemic compounds to the
corresponding enones. Tsuge Otohiko had reported the
HWE reactions of these racemic compounds using
DBU/LiBr system.7 However, we found it took a long
Scheme 4.
Table 1. CALB-catalyzed enantioselective acetylation of 2a–c
R
Yield of 3a–c (%) ee of 6a–c (%)b
Yield of 4a–c (%)
Yield of 5a–c (%)
Yield of 7a–c (%)
ee of 7a–cb (%)
Ea
Me
Et
Vinyl
40
42
35
99.1
95
95
48
45
51
70
65
63
86
79
85
98
95
97.1
\25
\19
\17
a E, the enantiomeric ratio, was roughly calculated based on the yields of 3a–c, 4a–c and the ee of 6a–c.
b Ee values were determined by chiral HPLC.

Y. Zhang et al. / Tetrahedron: Asymmetry 14 (2003) 63–70
Table 2. C. rugosa lipase-catalyzed enantioselective hydrolysis of 11a–i
65
Entry
R
Yield of 9a–i (%)
Yield of 11a–i (%)
Yield of 12a–i (%)
ee of 12a–ib (%)
Ea
1
2
3
4
5
6
7
8
9
C6H5
4-FC6H4
69
70
73
69
68
74
73
71
65
35
38
37
32
34
36
38
39
31
69
84
81
92
78
86
90
85
95
98.7
95.9
100
96.8
99.4
98.0
97.0
97.5
85.9
\100
\87
\100
\92
\100
\100
\100
\100
\19
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-BrC6H4
2-ClC6H4
2,4-Di-ClC6H3
2-Furyl
a E, the enantiomeric ratio, was roughly calculated based on the yields of 11a–i and the ee of 12a–i.
b Ee values were determined by chiral HPLC.
cally active d-hydroxy-b-ketoalkanephosphonates with
high ee more convenient. Consequently, optimization of
this method and its application in synthetic organic
chemistry are currently undergoing in our laboratory.
4. Experimental
IR spectra were recorded on a Shimadzu IR-440 spec-
trometer. EI mass spectra (MS) were run on a HP-
5989A mass spectrometer. 1H NMR spectra were
recorded on a Bruker AMX-330 (300 MHz) spectrome-
ter in CDCl3 and chemical shifts were reported in ppm
downfield relative to TMS (internal standard); 31P
NMR spectra were taken on the same spectrometer
using 80% phosphorus acid as external standard. The
melting point was not corrected.
Figure 1. X-Ray structure of compound 12f.
propyl ether for preparing enantiomerically pure 2-
hydroxy-2-aryethanephosphonates (Scheme 3).10
Intrigued by the satisfactory results obtained, and tak-
ing into account the structure similarity, we wished to
resolve those d-hydroxy-b-ketoalkanephosphonates
bearing aryl group via CRL-catalyzed hydrolysis in
diisopropyl ether (Scheme 4 and Table 2).
CALB (Novozym 435) was a gift from Novo Nor-
vodisk Co. C. rugosa lipase (901 units/mg) was pur-
chased from Sigma Chemical Co. The racemic
d-hydroxy-b-ketoalkanephosphonates were prepared
according to literature.7
Direct butyrylation of 10a–i using DCC/butyric acid
system afforded the butyryl derivatives 9a–i in 65–85%
yield. They could be enantioselectively hydrolyzed to
the corresponding (R)-alcohols in water-equilibrated
diisopropyl ether. In contrast with CALB, the catalytic
preference of CRL toward hydrolysis of the esters of
the secondary alcohols could not be accurately pre-
dicted. We determined the absolute configuration of the
hydrolyzed alcohols according to the X-ray structure of
compound 12f (Fig. 1) since it bears a bromine atom at
the 2-position of the phenyl ring. It showed that it was
of the (R)-configuration.
The chiral liquid chromatography system: Waters 515
HPLC pump; UV Waters 2487 dual l absorbance
detector, 254 nm; Penelson Network chromatography
interface NCI 900, Turbohrom Navigator data station
software; column dimensions: 0.46×25 cm; flow rate:
0.7 mL/min; eluent: hexane:isopropanol=9:1–8:2 (v/v).
4.1. General procedure for CALB-catalyzed acetylation
of racemic d-hydroxy-b-ketoalkanephosphonates 2a–c
To a stirred solution of hydroxyalkanephosphonate (1
mmol) in benzene (15 mL) was added vinyl acetate (2
mL). The reaction was started by addition of CALB
(100 mg). The mixture was maintained at 30°C. When
the reaction proceeded to certain conversion (within 50
h), the enzyme was filtered, washed with acetone (5
mL). The solvent was removed under reduced pressure
and the residue was subjected to flash chromatography
to furnish hydroxyalkanephosphonates and their
acetates. The yields are listed in Table 1.
It is a pity that the unreacted (S)-substrates (10a–i)
could not be directly applied to HWE reactions and we
are now engaged in enzymatic hydrolysis of these
butyryl derivatives.
3. Conclusion
In summary, the ready access to racemic starting mate-
rial coupled with their efficient and simple enzymatic
resolution here reported makes the preparation of opti-
4.1.1. (4S)-Diethyl 4-hydroxy-2-oxo-pentylphosphonate
1
3a. Colorless oil; [h]1D8=+33.2 (c 1.2, CHCl3); H NMR

66
Y. Zhang et al. / Tetrahedron: Asymmetry 14 (2003) 63–70
(300 MHz, CDCl3): l 4.18–4.28 (5H, m, CH
P(OCH2CH3)2), 3.10–3.18 (2H, dd, J=1.5, 23 Hz,
CH2P), 2.75–2.87 (3H, m, CH(OH)CH2CO), 1.34–1.39
(6H, t, J=6.9 Hz, P(OCH2CH3)2), 1.22–1.24 (3H, d,
J=6.45 Hz, CH
3CHOH); 31P NMR (120 MHz,
CDCl3): l 17.76; IR (film): 3404, 2980, 1714, 1446,
1394, 1372, 1249, 1164, 1026, 973 cm−1; EIMS (m/z):
239 (M++1) (2.06), 237 (2.55), 221 (21.64), 179 (27.28),
165 (88.38), 91 (100), 69 (81.22), 43 (80.12).
6
OH+
Anal. calcd for C10H19O5P: C, 48.00; H, 7.65. Found:
C, 47.79; H, 7.89.
6
6
6
6
4.1.6. (4S)-Diethyl 4-acetyloxy-2-oxo-5-hexenylphospho-
6
1
nate 4c. Colorless oil; [h]1D8=−1.3 (c 0.85, CHCl3); H
6
NMR (300 MHz, CDCl3): l 5.78–5.89 (1H, m,
CH2ꢀCH
(2H, m, CH2ꢀCH
3.06–3.15 (2H, dd, J=2.1, 22.7 Hz, CH2
(2H, m, CH2COCH2P), 2.04 (3H, s, CH3CO), 1.32–1.36
(6H, t, J=6.9 Hz, P(OCH2CH3 2
) ); 31P NMR (120
6
), 5.64–5.70 (1H, m, CH2ꢀCHꢁCH
), 4.10–4.20 (4H, m, P(OCH2
P), 2.97–3.02
6
), 5.18–5.33
6
6
CH3)2),
6
6
6
6
4.1.2. (4R)-Diethyl 4-acetyloxy-2-oxo-pentylphosphonate
MHz, CDCl3): l 17.36; IR (film): 2987, 1741, 1623,
1592, 1372, 1244, 1025, 971 cm−1; EIMS (m/z): 293
(M++1) (5.10), 233 (100), 203 (26.98), 179 (27.30), 123
(44.98), 94 (71.38). Anal. calcd for C12H21O6P: C, 49.30;
H, 7.24. Found: C, 49.41; H, 7.10.
1
4a. Colorless oil; [h]1D8=+4.0 (c 0.6, CHCl3); H NMR
(300 MHz, CDCl3):
CH
3.07–3.16 (2H, dd, J=2.1, 22.8 Hz, CH
(2H, m, CHCH2COCH2P), 2.01 (3H, s, CH3
1.39 (6H, t, J=7.2 Hz, P(OCH2CH3)2), 1.29–1.31 (2H,
d, J=6.3 Hz, CH3
CHCH2CO); 31P NMR (120 MHz,
l
5.27–5.34 (1H, m,
CH3)2),
2P), 2.81–3.03
CO), 1.34–
6
CH2COCH2P), 4.14–4.21 (4H, m, P(OCH6 2
6
6
6
6
4.2. General procedure for CALB-catalyzed hydrolysis
of 4-acetyloxy-2-oxo-phosphonates
6
CDCl3): l 17.76; IR (film): 2986, 1739, 1371, 1284,
1025, 966, 792 cm−1; EIMS (m/z): 237 (11.27), 221
(53.54), 197 (22.93), 179 (77.45), 151 (61.17), 123
(93.50), 69 (80.27), 43 (100).
To a stirred water-saturated diisopropyl ether (4 mL)
was added a mixture of the acetylated phosphonates
and 300 mg CALB. The solution was stirred at room
temperature until the starting material nearly disap-
peared (3 days or so). After filtration and washing with
5 mL CHCl3, the solvent was removed under reduced
pressure and the residue was subjected to flash chro-
matography to furnish the hydrolyzed products of
whose yields are listed in Table 1.
4.1.3. (4S)-4-Diethyl 4-hydroxy-2-oxo-hexylphosphonate
1
3b. Colorless oil; [h]1D8=+40 (c 0.75, CHCl3); H NMR
(300 MHz, CDCl3):
P(OCH2CH3)2), 399–4.11 (1H, m, CH
(2H, dd, J=1.5, 23 Hz, CH2P), 2.91 (1H, br, s, OH),
2.67–2.85 (2H, m, CH(OH)CH2CO), 1.48–1.55 (2H, m,
CH3CH2CHOH), 1.33–1.38 (3H, t, J=7.2 Hz,
P(OCH2CH3)2), 0.94–0.99 (3H, t, J=7.2 Hz,
CH3
l
4.11–4.21 (4H, m,
6
6
OH), 3.11–3.19
6
6
4.3. General procedure for HWE reactions of the chiral
d-hydroxy-b-ketoalkanephosphonates
6
6
CH2CHOH); IR (film): 3412, 2981, 1715, 1250,
1026, 975 cm−1; EIMS (m/z): 234 (M−H2O) (6.38), 223
(100), 195 (39.21), 179 (45.19), 167 (34.84), 151 (26.17),
123 (61.79). HRMS calcd for C10H19O4P (M−H2O):
234.10210. Found: 234.10578.
To substrates (40 mg) was added K2CO3 (300 mg), H2O
(0.6 mL) and benzaldehyde (0.6 mL), the mixture was
stirred and ethyl acetate (5 mL) and water (5 mL) was
added after the starting material disappeared (generally
within 5 h) as monitored by TLC. The aqueous phase
was extracted with ethyl acetate (2×5 mL). Dried with
anhydrous sodium sulfate, the solvent was removed
under reduced pressure and the residue was subjected to
flash chromatography. The yields of the reaction prod-
ucts are listed in Table 1.
4.1.4. (4R)-Diethyl 4-acetyloxy-2-oxo-hexylphosphonate
1
4b. Colorless oil; [h]1D8=+11.5 (c 0.6, CHCl3); H NMR
(300 MHz, CDCl3): l 5.17–5.21 (1H, m, CH
6
CH2-
CH3)2), 3.06–3.18
COCH2P), 2.87–2.89 (2H, d, J=6.3
2P), 2.06 (3H, s, CH3CO), 1.60–1.66 (2H, m,
CH3CH2CHCH2CO), 1.30–1.36 (6H, m, P(OCH2-
CH3)2), 0.88–0.93 (3H, t, J=7.5 Hz, CH6 3CH2CHCH2-
COCH2P), 4.10–4.19 (4H, m, P(OCH2
(2H, m, CHCH2
Hz, CH
6
6
6
6
4.3.1. (5S,1E)-5-Hydroxy-1-phenyl-1-hexen-3-one 6a.
Pale yellow oil; ee 99.1%; [h]1D5=+41 (c 0.65, CHCl3);
1H NMR (300 MHz, CDCl3): l 7.28, 7.62 (6H, m,
6
6
CO); IR (film): 2979, 1737, 1373, 1249, 1026 cm−1;
EIMS (m/z): 251 (8.96), 234 (56.52), 223 (27.78), 179
(100), 151 (55.66), 123 (83.78), 109 (34.75), 43 (57.06).
HRMS calcd for C12H23O6P: 294.12323. Found:
294.12583.
ArꢁH
4.30–4.40 (1H, m, CH
CH
6
+ArCH
6
), 6.74 (1H, d, J=16.5 Hz, ArCHꢀCH
6
),
6
OH), 2.64–2.95 (3H, OH
6
+
6
2CO), 1.284 (3H, d, J=6.6 Hz, CH3
6
CHOH); IR
(film): 3430, 1703, 1609, 1246, 1174 cm−1; EIMS (m/z):
190 (M+) (4.71), 145 (13.24), 131 (100), 103 (84.90), 43
(76.13), 102 (27.54). HRMS calcd for C12H14O2:
190.0994. Found: 190.0991.
4.1.5. (4R)-Diethyl 4-hydroxy-2-oxo-5-hexenylphospho-
1
nate 3c. Colorless oil; [h]1D8=+17.5 (c 0.85, CHCl3); H
NMR (300 MHz, CDCl3): l 5.30–5.35 (1H, m,
4.3.2. (5S,1E)-5-Hydroxy-1-phenyl-1-hepten-3-one 6b.
1
CH2ꢀCH
(1H, m, CH
3.123–3.199 (2H, d, J=23 Hz, CH2
J=5.4 Hz, CHOHCH2CO), 1.338–1.38 (6H, t, J=7.2
Hz, P(OCH2CH3 2
) ); 31P NMR (120 MHz, CDCl3): l
6
), 5.13–5.35 (2H, 2dd, CH2
OH), 4.137–4.212 (4H, m, P(OCH
P), 2.85–2.87 (2H, d,
6
ꢀCH), 4.589–4.612
Colorless oil; ee 95%; [h]2D5=+50.7 (c 1.65, CHCl3); H
6
6
2CH3)2),
NMR (300 MHz, CDCl3): l 7.39–7.60 (6H, m, ArꢁH
ArCH), 6.74 (1H, d, J=16.2 Hz, ArCHꢀCH), 4.05–4.13
(1H, m, CHOH), 2.73–2.94 (2H, m, CH2CO), 1.51–1.64
(2H, m, CH3CH2CHOH), 1.03 (3H, t, J=7.2 Hz,
6 +
6
6
6
6
6
6
6
6
17.72; IR (film): 3402, 1714, 1647, 1395, 1246, 1024, 973
cm−1; EIMS (m/z): 250 (M+) (2.52), 233 (3.15), 194
(85.49), 179 (70.33), 151 (47.51), 125 (100), 97 (62.14).
CH6 3CH2CHOH); IR (film): 3447, 2966, 2932, 1716,
1685, 1652, 1608, 977, 750, 714, 690 cm−1; EIMS (m/z):
204 (M+) (3.32), 186 (6.81), 146 (19.04), 131 (100), 103

Y. Zhang et al. / Tetrahedron: Asymmetry 14 (2003) 63–70
67
(34.12), 77 (18.37). HRMS calcd for C13H16O2:
204.1150. Found: 204.1106.
J=7.8 Hz, ArH
4.04–4.21 (4H, m, P(OCH2
Hz, ArCHCH2), 3.09 (2H, d, J=22.8 Hz, CH2P), 3.05–
3.13 (1H, m, ArCHCH2), 2.33 (3H, ArCH3), 2.26 (2H,
t, J=7.2 Hz, CH3CH2CH2CO), 1.58–1.65 (2H, m,
CH3CH2CH2CO), 1.27–1.36 (6H, m, P(OCH2CH3)2),
0.91 (3H, t, J=7.2 Hz, CH
3CH2CH2CO); 31P NMR
(120 MHz, CDCl3): l 19.48; IR (film): 2981, 2935,
1734, 1502, 1254, 1026, 973 cm−1; EIMS (m/z): 384
(M+) (2.12), 366 (5.10), 313 (100), 296 (12.49), 179
(29.64), 158 (81.12), 145 (60.17), 119 (83.73), 91 (20.98),
77 (2.99). HRMS calcd for C19H29O6P: 384.1702.
Found: 384.1707.
6
), 6.18 (1H, dd, J=8.4 Hz, ArCH
6 ),
6
CH3)2), 3.30 (1H, dd, J=8.4
6
6
6
4.3.3. (5R,1E)-5-Hydroxy-1-phenyl-1,6-heptadien-3-one
1
6c. Colorless oil; [h]1D6=+33 (c 0.25, CHCl3); H NMR
6
6
6
(300 MHz, CDCl3): l 7.36–7.62 (6H, m, ArꢁH
6
+ArCH
), 5.89–6.00 (1H, m,
ꢁCHOH), 5.16–5.39 (2H, 2d, J=17.1, 17.4 Hz,
ꢀCHꢁCHOH), 4.69–4.70 (1H, m, CHOH), 3.32
(1H, s, OH), 2.85–2.98 (2H, m, CH2ꢀCHꢁCHOHCH2);
6 ),
6
6.75 (1H, d, J=16.2 Hz, ArCHꢀCH
CH2ꢀCH
CH2
6
6
6
6
6
IR (film): 3437, 1733, 1678, 1646, 1601, 1513, 1256,
1174 cm−1; EIMS (m/z): 202 (M+) (1.32), 145 (20.38),
131 (100), 103 (60.55), 78 (28.65). HRMS calcd for
C13H14O2: 202.0994. Found: 202.0971.
4.4.4. Diethyl 4-butyryloxy-2-oxo-4-(4-methoxylphenyl)-
butylphosphonate 9d. Colorless oil; 1H NMR (300 MHz,
4.4. General procedure for the preparation of diethyl
4-butyryloxyl-4-aryl-2-oxo-butylphosphonates
CDCl3): l 7.29 (2H, d, J=6.6 Hz, ArH
J=6.6 Hz, ArH), 6.181 (1H, dd, J=8.4 Hz, ArCH
4.08–4.17 (4H, m, P(OCH2CH3)2), 3.76 (3H, ArOCH3
3.08–3.31 (2H, m, ArCHCH
CH2P), 2.280 (2H, t, J=7.5 Hz, CH3CH2CH2
1.59–1.70 (2H, m, CH3CH2CH2CO), 1.24–1.37 (6H, m,
P(OCH2CH3)2), 0.94 (3H, t, J=7.2 Hz,
CH
3CH2CH2CO); 31P NMR (120 MHz, CDCl3): l
6
), 6.85 (2H, d,
6
6
),
),
In a 25 mL bottle was added substrates (1 mmol),
n-butyric acid (106 mg, 1.2 mmol) and DCC (248 mg,
1.2 mmol), methylene chloride (10 mL), the mixture
was cooled to 0°C and DMAP (10 mg) was added.
After the starting material was consumed, ether (10
mL) was added, and the precipitate was filtered off. The
solvent was removed under reduced pressure and the
residue was subjected to flash chromatography to fur-
nish the corresponding butyryl derivatives of which
yields are listed in Table 2.
6
6
6
2), 3.08 (2H, d, J=21.6 Hz,
CO),
6
6
6
6
19.51; IR (film): 2981, 2937, 2842, 1727, 1599, 1254,
1175, 1027, 974 cm−1; EIMS (m/z): 400 (M+) (1.55), 329
(33.09), 312 (19.02), 283 (7.55), 174 (57.14), 161 (100),
135 (39.74). HRMS calcd for C19H29O7P: 400.1651.
Found: 400.1689.
4.4.1. Diethyl 4-butyryloxy-2-oxo-4-phenylbutylphospho-
1
nate 9a. Colorless oil; H NMR (300 MHz, CDCl3): l
4.4.5. Diethyl 4-butyryloxy-2-oxo-4-(4-chlorophenyl)-
7.25–7.39 (5H, m, ArH
ArCH
(4H, m, CH2
COCH2CH2CH3), 1.56–1.71 (2H, m, COCH2CH2
1.24–1.33 (6H, m, P (OCH2CH3)2), 0.87 (3H, t, J=6.9
Hz, COCH2CH2CH3
); 31P NMR (120 MHz, CDCl3): l
6
), 6.18 (1H, dd, J=8.4 Hz,
2CH3)2), 3.02–3.28
), 2.24 (2H, t, J=7.2 Hz,
CH3),
1
butylphosphonate 9e. Colorless oil; H NMR (300 MHz,
6
), 4.02–4.14 (4H, m, P (OCH
6
CDCl3): l 7.31 (4H, s, ArH
ArCH), 4.04–4.20 (4H, m, P(OCH
(1H, m, ArCHCH2), 3.08 (2H, d, J=23.1 Hz, CH2
3.11–3.14 (1H, m, ArCHCH2), 2.28 (2H, t, J=7.2 Hz,
CH3CH2CH2CO), 1.57–1.67 (2H, m, CH3CH2CH2CO),
1.26–1.36 (6H, m, P(OCH2CH3)2), 0.90 (3H, t, J=7.2
Hz, CH
3CH2CH2CO); 31P NMR (120 MHz, CDCl3): l
6
), 6.159 (1H, dd, J=6.9 Hz,
2CH3)2), 3.24–3.30
P),
6
COCH2
6
6
6
6
6
6
6
6
6
6
6
6
19.36; IR (film): 3462, 2972, 2936, 2978, 1735, 1255,
1025, 973 cm−1; EIMS (m/z): 370 (M+) (0.62), 352
(5.16), 299 (100.00), 253 (11.86), 195 (13.61), 179
(33.79), 144 (56.14), 131 (42.48), 105 (79.68), 77 (17.41).
HRMS calcd for C18H27O6P: 370.1545. Found:
370.1512.
6
6
19.144; IR (film): 2984, 2933, 2910, 1689, 1610, 1253,
1048, 1026, 974 cm−1; EIMS (m/z): 333 (4.53), 317
(100), 287 (11.27), 178 (31.63), 165 (43.73), 137 (11.40),
102 (13.84). HRMS calcd for C14H19ClO5P (M−COPr-
n): 333.0659. Found: 333.0675.
4.4.2. Diethyl 4-butyryloxy-2-oxo-4-(4-fluorophenyl)-
butylphosphonate 9b. Colorless oil; 1H NMR (300 MHz,
CDCl3): l 7.34–7.38 (2H, m, ArH), 7.02–7.13 (2H, m,
4.4.6. Diethyl 4-butyryloxy-2-oxo-4-(2-bromophenyl)-
1
butylphosphonate 9f. Colorless oil; H NMR (300 MHz,
ArH
m, P(OCH2
(2H, d, J=22.8 Hz, CH2P), 2.30 (2H, t, J=7.2 Hz,
CH3CH2CH2CO), 1.57–1.69 (2H, m, CH3CH2CH2CO),
1.25–1.43 (6H, m, P(OCH2CH3)2), 0.92 (3H, t, J=7.2
Hz, CH3
CH2CH2CO); 31P NMR (120 MHz, CDCl3): l
6
), 6.17 (1H, dd, J=5.7 Hz, ArCH
6
), 4.05–4.22 (4H,
3
4
CDCl3): l 7.58 (1H, dd, JH–H=7.8 Hz, JH–H=1.2 Hz,
6
CH3)2), 3.05–3.37 (2H, m, ArCHCH2
6
), 3.09
ArH
ArH
ArH
ArH
m, P(OCH
COCH2), 2.34 (2H, t, J=7.2 Hz, CH3CH2CH2
1.58–1.71 (2H, m, CH3CH2
m, P(OCH2CH3)2), 0.934 (3H, t, J=7.5 Hz,
CH
6
), 7.36 (1H, dd, 3JH–H=7.8 Hz, 4JH–H=2.1 Hz,
), 7.30 (1H, dt, 3JH–H=7.5 Hz, 4JH–H=1.2 Hz,
), 7.15 (1H, dt, 3JH–H=7.8 Hz, 4JH–H=1.8 Hz,
6
6
6
6
6
6
), 6.46 (1H, dd, J=7.5 Hz, ArCH
6
), 4.09–4.20 (4H,
6
6
2CH3)2), 3.04–3.24 (4H, m, ArCHCH2
6
19.19; IR (film): 3462, 2982, 2937, 2878, 1733, 1511,
1234, 1029, 974 cm−1; EIMS (m/z): 388 (M+) (0.86),
317 (100), 300 (8.47), 271 (9.47), 179 (26.70), 162
(25.09), 149 (37.12), 123 (69.89), 109 (12.941). HRMS
calcd for C18H26FO6P: 388.1451. Found: 388.1472.
6
6
CO),
6
CH2CO), 1.24–1.364 (6H,
6
6
3CH2CH2CO); 31P NMR (120 MHz, CDCl3): l
19.61; EIMS (m/z): 449 (M++1) (1.62), 364 (43.49), 363
(39.32), 362 (42.80), 361 (50.15), 281 (100), 253 (20.81),
43 (38.14); IR (film): 2970, 2936, 2877, 1743, 1726,
1257, 1027, 971 cm−1.
4.4.3. Diethyl 4-butyryloxy-2-oxo-4-(4-methylphenyl)-
1
butylphosphonate 9c. Colorless oil; H NMR (300 MHz,
CDCl3): l 7.28 (2H, d, J=8.1 Hz, ArH6 ), 7.15 (2H, d,

68
Y. Zhang et al. / Tetrahedron: Asymmetry 14 (2003) 63–70
4.4.7. Diethyl 4-butyryloxy-2-oxo-4-(2-chlorophenyl)-
ArH), 5.20 (1H, dd, J=9.0 Hz, ArCH
m, P (OCH2CH3)2), 3.01–3.20 (4H, m, CH2
1.27–1.38 (6H, m, P (OCH2CH3 2
) ); 31P NMR (120
MHz, CDCl3): l 19.67; IR (film): 3381, 2985, 1716,
1394, 1251, 1047, 1025, 969 cm−1; EIMS (m/z): 300
(M+) (3.63), 283 (58.26), 195 (74.06), 167 (46.28), 152
(52.86), 139 (50.42), 125 (100.00), 105 (86.79), 97
(68.07), 77 (79.56).
6
), 4.10–4.20 (4H,
butylphosphonate 9g. Colorless oil; 1H NMR (300 MHz,
6
6
COCH2),
6
CDCl3): l 7.22–7.39 (4H, m, ArH
J=8.1 Hz, ArCH
3.37 (2H, d, J=23.1 Hz, CH
ArCHCH2), 2.32 (2H, t, J=7.8 Hz, CH3CH2CH2
1.61–1.68 (2H, m, CH3CH2CH2CO), 1.26–1.37 (6H, m,
P(OCH2CH3)2), 0.93 (3H, t, J=7.2 Hz, CH3CH2CH2-
6
), 6.51 (1H, dd,
), 4.10–4.21 (4H, m, P(OCH2CH3)2),
2P), 3.09–3.19 (2H, m,
CO),
6
6
6
6
6
6
6
6
6
CO); 31P NMR (120 MHz, CDCl3): l 19.27; IR (film):
3466, 2981, 2912, 2877, 1726, 1255, 1026, 973 cm−1;
EIMS (m/z): 405 (M++1) (1.02), 333 (13.35), 317
(81.00), 281 (100.00), 253 (28.06), 225 (27.04), 179
(18.38), 165 (31.42), 139 (22.44), 76 (3.82). HRMS calcd
for C18H26ClO6P: 404.1156. Found: 404.1174.
4.5.2. (4R)-Diethyl 4-hydroxy-2-oxo-4-(4-fluorophenyl)-
butylphosphonate 11b. Colorless oil; [h]2D7=+42.7 (c
1.55, CHCl3); 1H NMR (300 MHz, CDCl3): l 7.32–7.37
(2H, m, ArH), 3.99–7.05 (2H, m, ArH), 5.164 (1H, dd,
J=8.4 Hz, ArCH
6
), 4.08–4.18 (4H, m, P (OCH
3.14 (2H, d, JP–H=23.1 Hz, CH2P), 2.93–3.13 (2H, m,
CHCH2), 1.330 (6H, t, J=7.2 Hz, P(OCH2CH3 2
) ); 31P
6 2CH3)2),
2
6
4.4.8. Diethyl 4-butyryloxy-2-oxo-4-(2,4-dichlorophenyl)-
6
6
butylphosphonate 9h. Colorless oil; 1H NMR (300 MHz,
NMR (120 MHz, CDCl3): l 19.50; IR (film): 3375,
2987, 2912, 1716, 1511, 1223, 1026, 973 cm−1; EIMS
(m/z): 318 (M+) (2.50), 301 (100.00), 179 (16.81), 152
(19.33), 123 (47.73), 109 (15.36), 97 (39.25), 77 (8.92).
Anal. calcd for C14H20FO5P: C, 52.83; H, 6.33. Found:
C, 52.43; H, 6.16.
CDCl3): l 7.21–7.44 (3H, m, ArH
J=8.7 Hz, ArCH
3.34 (2H, d, J=22.8 Hz, CH
ArCHCH2), 2.29 (2H, t, J=7.5 Hz, CH3CH2CH2
1.59–1.66 (2H, m, CH3CH2CH2CO), 1.32 (6H, t, J=6.9
Hz, P(OCH2CH3)2), 0.92 (3H, t, J=7.5 Hz,
CH3
CH2CH2CO); 31P NMR (120 MHz, CDCl3): l
6
), 6.430 (1H, dd,
), 4.06–4.21 (4H, m, P(OCH2CH3)2),
2P), 3.07–3.17 (2H, m,
CO),
6
6
6
6
6
6
6
6
19.27; IR (film): 2980, 2936, 2877, 1742, 1724, 1255,
1048, 1026, 971 cm−1; EIMS (m/z): 420 (1.05), 367
(12.88), 315 (100.00), 287 (16.46), 259 (16.71), 199
(27.33), 179 (14.74), 136 (13.80), 123 (7.58), 109 (10.43),
78 (2.24). HRMS calcd for C18H25Cl2O6P: 438.0766.
Found: 438.0798.
4.5.3. (4R)-Diethyl 4-hydroxy-2-oxo-4-(4-methylphenyl)-
butylphosphonate 11c. Colorless oil; [h]2D7=+38.9 (c 0.9,
1
CHCl3); H NMR (300 MHz, CDCl3): l 7.27 (2H, d,
J=7.8 Hz, ArH), 7.22 (2H, d, J=7.8 Hz, ArH), 5.16
(1H, dd, J=9.0 Hz, ArCH
(OCH2CH3)2), 2.88–3.19 (4H, m, CH2
(3H, s, CH3Ar), 1.31–1.37 (6H, m, P(OCH2CH3 2
6
), 4.106–4.21 (4H, m, P
COCH2), 2.33
) ); 31P
6
6
6
6
6
4.4.9. Diethyl 4-butyryloxy-2-oxo-4-(2-furyl)-butylphos-
NMR (120 MHz, CDCl3): l 19.86; IR (film): 3379,
2985, 2912, 1716, 1394, 1253, 1025, 968 cm−1; EIMS
(m/z): 314 (M+) (32.90), 194 (87.27), 167 (57.74), 152
(68.87), 125 (100.00), 119 (99.84), 97 (49.34), 91 (72.38),
77 (34.26). HRMS calcd for C15H23O5P: 314.1283.
Found: 314.1282.
1
phonate 9i. Colorless oil; H NMR (300 MHz, CDCl3):
l 7.36–7.38 (1H, m, ArH
4.09–4.19 (4H, m, P(OCH2
ArCHCH2), 3.12 (2H, d, J=22.8 Hz, CH2
t, J=7.5 Hz, CH3CH2CH2CO), 1.58–1.67 (2H, m,
CH3CH2CH2CO), 1.30–1.36 (6H, m, P(OCH2CH3)2),
0.90 (3H, t, J=7.2 Hz, CH
3CH2CH2CO); 31P NMR
6
), 6.27–6.39 (3H, ArH
CH3)2), 3.22–3.43 (2H, m,
P), 2.25 (2H,
6 , ArCH6 ),
6
6
6
6
6
6
6
4.5.4. (4R)-Diethyl 4-hydroxy-2-oxo-4-(4-methoxyl-
phenyl)butylphosphonate 11d. Colorless oil; [h]2D7=+40.1
(120 MHz, CDCl3): l 19.26; IR (film): 2980, 1737,
1253, 1024, 973 cm−1; EIMS (m/z): 360 (M+) (3.01), 289
(100.00), 273 (13.20), 193 (12.04), 179 (67.55), 151
(38.89), 123 (39.46), 109 (17.59), 71 (15.64), 65 (12.57).
HRMS calcd for C16H25O7P: 360.1338. Found:
360.1319.
1
(c 1.85, CHCl3); H NMR (300 MHz, CDCl3): l 7.302
(2H, d, J=9.3 Hz, ArH), 6.89 (2H, d, J=9.0 Hz, ArH),
5.15 (1H, dd, J=7.5 Hz, ArCH
(OCH2CH3)2), 3.81 (3H, s, OCH3
22.8 Hz, CH2P), 2.99–3.08 (2H, m, CHCH2
t, J=7.2 Hz, P(OCH2CH3 2
) ); 31P NMR (120 MHz,
6 ), 4.13–4.20 (4H, m, P
2
6
6
), 3.15 (2H, d, JP–H
=
6
6
), 1.35 (6H,
6
4.5. General procedure of CRL-catalyzed enantioselec-
tive hydrolysis for the preparation of optical active d-
hydroxy-b-ketoalkanephosphonates
CDCl3): l 19.62; IR (film): 3384, 2985, 2935, 2910,
1714, 1514, 1249, 1029, 972 cm−1; EIMS (m/z): 330
(M+) (0.49), 194 (11.02), 152 (20.63), 136 (63.88), 135
(100.00), 125 (37.77), 109 (23.21), 97 (30.75), 77 (34.99),
65 (22.76).
To 1.2 M aqueous MgCl2–saturated diisopropyl ether
(4 mL) were added substrates (100 mg), and the reac-
tion was started by adding crude CRL (100 mg). When
the mixture was stirred about 48 h, filtered off the
enzymes and washed with 5 mL ethyl acetate. The
combined solvent was removed under reduced pressure
and the residue was subjected to flash chromatography
to afford unreacted esters and the hydrolyzed alcohols
of which the yields are listed in Table 2.
4.5.5. (4R)-Diethyl 4-hydroxy-2-oxo-4-(4-chlorophenyl)-
butylphosphonate 11e. Colorless oil; [h]2D7=+41.2 (c
1.95, CHCl3); 1H NMR (300 MHz, CDCl3): l 7.31 (4H,
s, ArH), 5.16 (1H, dd, J=8.7 Hz, ArCH
(4H, m, (OCH2CH3)2), 2.97–3.18 (4H, m,
CH2COCH2), 1.30–1.35 (6H, m, P(OCH2CH3 2
) ); 31P
6 ), 4.10–4.18
P
6
6
6
6
NMR (120 MHz, CDCl3): l 19.58; IR (film): 3371,
2985, 1716, 1248, 1025, 972 cm−1; EIMS (m/z): 334
(M+) (1.00), 317 (100.00), 195 (36.13), 179 (19.49), 152
(12.25), 139 (22.26), 125 (17.97), 97 (14.54), 77 (12.49).
4.5.1. (4R)-Diethyl 4-hydroxy-2-oxo-4-phenylbutylphos-
phonate 11a. Colorless oil; [h]2D7=+41.6 (c 1.8, CHCl3);
1H NMR (300 MHz, CDCl3): l 7.29–7.43 (5H, m,

Y. Zhang et al. / Tetrahedron: Asymmetry 14 (2003) 63–70
69
4.5.6. (4R)-Diethyl 4-hydroxy-2-oxo-4-(2-bromophenyl)-
4.6. HWE reactions of diethyl 4-hydroxy-2-oxo-4-(2-
aryl)-butylphosphonate
butylphosphonate 11f. Colorless oil; [h]2D5=+69.2 (c 1.25,
1
CHCl3); H NMR (300 MHz, CDCl3): l 7.633 (1H, dd,
4
3JH–H=7.8 Hz, JH–H=1.5 Hz, ArH
6
), 7.542 (1H, dd,
The procedures are similar with that of the aliphatic
counterparts. The yields of these reactions are listed in
Table 2.
3JH–H=7.8 Hz, 4JH–H=1.2 Hz, ArH
3JH–H=7.2 Hz, 4JH–H=0.6 Hz, ArH
3JH–H=7.5 Hz, 4JH–H=1.8 Hz, ArH
J=9.3 Hz, ArCH
2.80–3.22 (4H, m, ArCHCH2
m, P(OCH2CH3 2
6
), 7.34 (1H, dt,
), 7.13 (1H, dt,
), 5.49 (1H, dd,
6
6
6
), 4.10–4.20 (4H, m, P(OCH2
COCH2), 1.31–1.37 (6H,
) ); 31P NMR (120 MHz, CDCl3): l
6
CH3)2),
4.6.1. (5R,1E)-5-Hydroxy-1,5-diphenyl-1-penten-3-one
12a. Colorless oil; [h]2D7=+67.1 (c 1.05, CHCl3); 1H
6
6
6
NMR (300 MHz, CDCl3): l 7.51–7.59 (3H, m, ArH
ArCH
Hz, ArCHꢀCH
3.09 (2H, dd, J=7.2 Hz, CHCH2
6
,
19.56; IR (film): 3371, 2985, 1716, 1248, 1025, 972 cm−1;
EIMS (m/z): 379 (M+) (2.81), 362 (36.21), 300 (12.92),
281 (18.47), 194 (93.81), 185 (72.57), 167 (48.02), 152
(17.97), 125 (100.00), 97 (64.29), 77 (66.83). Anal. calcd
for C14H20BrO5P: C, 44.35; H, 5.32. Found: C, 44.41;
H, 5.50.
6
ꢀ), 7. 29–7.44 (8H, m, ArH
6
), 6.73 (1H, d, J=16.2
CO), 5.27 (1H, t, J=6.3 Hz, ArCH
6
6
),
6
CO); IR (film): 3445,
2971, 2937, 1662, 1625, 1492, 1091, 1014, 977, 831
cm−1; EIMS (m/z): 252 (M+) (3.43), 160 (9.86), 145
(37.10), 131 (100.00), 120 (27.81), 105 (65.19), 103
(61.98), 77 (75.26), 51 (33.15).
4.6.2. (5R,1E)-5-Hydroxy-5-(4-fluorophenyl)-1-phenyl-1-
penten-3-one 12b. Colorless solid; mp 108–109°C;
[h]2D7=+59.9 (c 1.1, CHCl3); 1H NMR (300 MHz,
4.5.7. (4R)-Diethyl 4-hydroxy-2-oxo-4-(2-chlorophenyl)-
butylphosphonate 11g. Colorless oil; [h]2D5=+74.7 (c 1.5,
1
CHCl3); H NMR (300 MHz, CDCl3): l 7.65 (1H, d,
CDCl3): l 7.40–7.60 (8H, m, ArH
J=8.1 Hz, ArH), 6.74 (1H, d, J=16.2 Hz,
ArCHꢀCHCO), 5.25 (1H, s, ArCH), 3.07 (2H, dd,
J=12.0 Hz, CHCH2CO); IR (film): 3401, 2925, 1646,
6 , ArCH6 ꢀ), 7.06 (2H, t,
J=5.4 Hz, ArH), 7.23–7.36 (3H, m, ArH
dd, J=9.9 Hz, ArCH), 4.12–4.22 (4H, m,
(OCH2CH3)2), 2.85–3.23 (4H, m, CH2COCH2), 1.32–
1.38 (6H, m, P(OCH2CH3 2
) ); 31P NMR (120 MHz,
6 ), 5.559 (1H,
6
6
P
6
6
6
6
6
6
6
1602, 1222, 982, 749, 692 cm−1; EIMS (m/z): 270 (M+)
(3.27), 233 (7.71), 145 (69.57), 131 (100.00), 123 (85.33),
103 (93.75), 95 (49.78), 91 (9.98), 77 (58.16), 65 (2.97).
HRMS calcd for C15H15FO2: 270.10561. Found:
270.10963.
CDCl3): l 19.56; IR (film): 3360, 2985, 2933, 2911,
1718, 1248, 1047, 1027, 972 cm−1; EIMS (m/z): 334
(M+) (0.21), 317 (35.85), 281 (9.19), 195 (100.00), 152
(25.58), 139 (53.71), 125 (25.58), 97 (21.03), 77 (16.30).
Anal. calcd for C14H20ClO5P: C, 50.23; H, 6.02. Found:
C, 50.44; H, 6.27.
4.6.3. (5R,1E)-5-Hydroxy-5-(4-methylphenyl)-1-phenyl-
1-penten-3-one 12c. White solid; mp 105–107°C; [h]2D7=
1
+79.6 (c 0.5, CHCl3); H NMR (300 MHz, CDCl3): l
4.5.8. Diethyl 4-hydroxy-2-oxo-4-(2,4-dichlorophenyl)-
7.03–7.77 (10H, m, ArH
Hz, ArCHꢀCH
3.08–3.11 (2H, m, CHCH
6
, ArCH
CO), 5.24 (1H, dd, J=7.5 Hz, ArCH
2CO), 2.40 (3H, s, CH3Ar);
6
), 6.74 (1H, d, J=16.2
butylphosphonate 11h. Colorless oil; [h]2D5=+68.7 (c 0.7,
6
6
),
1
CHCl3); H NMR (300 MHz, CDCl3): l 7.59 (1H, d,
6
6
J=8.7 Hz, ArH), 7.27–7.34 (2H, m, ArH
dd, J=7.8 Hz, ArCH), 4.11–4.18 (4H, m,
(OCH
2CH3)2), 3.18 (2H, d, 2JP–H=23.1 Hz, CH2
2.80–3.05 (2H, m, CHCH2
Hz, 4JP–H=0.9 Hz, P(OCH2CH3 2
6
), 5.49 (1H,
IR (film): 3456, 3024, 1647, 1448, 1183, 979, 812, 747,
693 cm−1; EIMS (m/z): 266 (M+) (2.20), 247 (11.07),
233 (17.21), 145 (79.69), 131 (88.37), 119 (100.00), 103
(91.35), 91 (88.47), 77 (47.83), 65 (21.82). Anal. calcd
for C18H18O2: C, 81.17; H, 6.81. Found: C, 80.97; H,
6.92.
6
P
P),
6
6
3
6
), 1.34 (6H, dt, JH–H=6.9
6
) ); 31P NMR (120
MHz, CDCl3): l 19.56; IR (film): 3360, 2985, 2933,
2911, 1718, 1248, 1047, 1027, 972 cm−1; EIMS (m/z):
334 (M+) (0.21), 317 (35.85), 281 (9.19), 195 (100.00),
152 (25.58), 139 (53.71), 125 (25.58), 97 (21.03), 77
(16.30). Anal. calcd for C14H19Cl2O5P: C, 45.55; H,
5.19. Found: C, 45.52; H, 5.32.
4.6.4.
(5R,1E)-5-Hydroxy-5-(4-methoxyphenyl)-1-
phenyl-1-penten-3-one 12d. White powder; mp 116–
117°C; [h]2D7=+51.0 (c 0.95, CHCl3); 1H NMR (300
MHz, CDCl3): l 7.52–7.60 (3H, m, ArH
7.42 (3H, m, ArH), 7.35 (2H, d, J=8.4 Hz, ArH
(2H, d, J=9.0 Hz, ArH), 6.74 (1H, d, J=16.2 Hz,
ArCHꢀCHCO), 5.20–5.23 (1H, m, ArCH), 3.18 (3H, s,
OCH3), 3.07–3.10 (2H, m, CHCH2CO); IR (film): 3509,
6
, ArCH
6
), 7.40–
6
6
), 6.91
6
4.5.9. Diethyl 4-hydroxy-2-oxo-4-(2-furyl)-butylphospho-
6
6
1
nate 11i. Colorless oil; [h]2D5=+28.1 (c 1.45, CHCl3); H
6
6
3
NMR (300 MHz, CDCl3): l 7.38 (1H, dd, JH–H=28.2
3055, 3025, 2938, 2839, 1645, 1514, 1247, 1181, 1035,
980, 838, 817, 748 cm−1; EIMS (m/z): 282 (M+) (2.24),
264 (8.17), 145 (47.88), 135 (100.00), 103 (66.44), 92
(14.96), 77 (60.40), 65 (11.84). Anal. calcd for
C18H18O3: C, 76.57; H, 6.43. Found: C, 76.74; H, 6.92.
4
Hz, JH–H=0.6 Hz), 6.30–6.35 (2H, m, ArH), 5.21 (1H,
d, J=9.0 Hz, ArCH
P(OCH2CH3)2), 3.09–3.25 (4H, m, CH2
1.39 (6H, m, P(OCH2CH3 2
) ); 31P NMR (120 MHz,
6
), 4.13–4.22 (4H, m,
6
6
COCH2), 1.33–
6
6
CDCl3): l 19.76; IR (film): 3366, 2986, 2912, 1718,
1247, 1024, 973 cm−1; EIMS (m/z): 290 (M+) (8.02), 273
(100.00), 244 (11.02), 195 (28.75), 179 (14.81), 152
(12.49), 121 (19.88), 97 (25.43), 65 (8.54). Anal. calcd
for C12H19O6P: C, 49.66; H, 6.60. Found: C, 49.60; H,
6.75.
4.6.5. (5R,1E)-5-Hydroxy-5-(4-chlorophenyl)-1-phenyl-1-
penten-3-one 12e. Colorless solid; mp 130–131°C;
[h]2D7=+58.6 (c 1.3, CHCl3); 1H NMR (300 MHz,
CDCl3): l 7.26–7.60 (10H, m, ArH
6 , ArCH6 ꢀ), 6.73 (1H,
d, J=16.2 Hz, ArCHꢀCHCO), 5.21–5.29 (1H, m,
6

70
Y. Zhang et al. / Tetrahedron: Asymmetry 14 (2003) 63–70
ArCH
6
), 3.05–3.11 (2H, m, CHCH2
6
CO); IR (film): 3393,
Hz, ArCHꢀCH
(1H, d, J=6.9 Hz, ArCH
CHCH2
6
CO), 6.34 (2H, d, J=7.8 Hz, ArH
6 ), 5.29
3026, 2928, 1648, 1608, 981, 749, 694 cm−1; EIMS
(m/z): 268 (7.80), 233 (12.78), 145 (47.88), 145 (72.70),
139 (61.43), 131 (100.00), 115 (11.27), 111 (26.54), 91
(9.86), 77 (96.64), 63 (11.59). HRMS calcd for
C17H15ClO2: 286.0761. Found: 286.0780.
6
), 3.15–3.35 (2H, m,
6
CO); IR (film): 3430, 3120, 3084, 2923, 1653,
1609, 1181, 1012, 979, 748, 691 cm−1; EIMS (m/z): 242
(M+) (10.84), 205 (27.24), 145 (27.72), 131 (100.00), 110
(91.33), 103 (66.33), 97 (22.53), 91 (19.11), 77 (51.33),
65 (8.66). HRMS calcd for C15H14O3: 242.0943. Found:
242.0908.
4.6.6. (5R,1E)-5-Hydroxy-5-(2-bromophenyl)-1-phenyl-1-
penten-3-one 12f. Colorless solid; mp 86–87°C; [h]2D7=
+121.2 (c 0.95, CHCl3); 1H NMR (300 MHz, CDCl3): l
7.13–7.71 (10H, m, ArH
Hz, ArCHꢀCHCO), 5.55 (1H, dd, J=9.6 Hz, ArCH
3.30 (1H, dd, J=17.4 Hz, CHCH2CO), 2.87 (1H, dd,
J=17.4 Hz, CHCH2CO); IR (film): 3458, 3062, 3028,
2910, 1654, 1608, 1176, 1095, 1068, 1023, 977, 753, 689
cm−1; EIMS (m/z): 313 (2.24), 251 (56.01), 233 (16.10),
185 (47.86), 145 (50.26), 131 (100.00), 103 (83.75), 91
(14.54), 77 (76.53), 65 (5.14). Anal. calcd for
C17H15BrO2: C, 61.64; H, 4.56. Found: C, 61.65; H,
4.80.
6
, ArCH
6
ꢀ), 6.75 (1H, d, J=15.9
Acknowledgements
6
6
),
6
6
The project was supported by the National Nature
Science Foundations of China (Grant. No. 20072052
and 29832050).
References
1. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89,
863–927.
4.6.7. (5R,1E)-5-Hydroxy-5-(2-chlorophenyl)-1-phenyl-1-
penten-3-one 12g. Colorless oil; mp 108–109°C; [h]2D7=
1
2. (a) Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.;
Ogawa, Y. J. Am. Chem. Soc. 1988, 110, 4685–4696; (b)
Flack, J. R.; Abdali, A.; Wittenberger, S. J. J. Chem.
Soc., Chem. Commun. 1990, 953–955; (c) Kerdesky, F. A.
J.; Schmift, S. P.; Brooks, D. W. J. Org. Chem. 1993, 58,
3516–3520.
3. (a) Rosen, T.; Heathcock, C. H. J. Am. Chem. Soc. 1985,
107, 3731–3733; (b) Karanewsky, D. S.; Malley, M. F.;
Gougoutas, J. Z. J. Org. Chem. 1991, 56, 3744–3747; (c)
Altenbach, H. J.; Holzapfel, W. Angew. Chem., Int. Ed.
Engl. 1990, 29, 67–78; (d) Narkunan, K.; Nagarajan, M.
J. Org. Chem. 1994, 59, 6386–6390; (e) Kojina, K.; Saito,
S. Synthesis 1992, 949–950; (f) Koskinen, A. M. P.;
Krische, M. J. Synlett 1990, 665–666; (g) Berkowitz, D.
B.; Eggen, M.; Shen, Q.; Shoemaker, R. K. J. Org. Chem.
1996, 61, 4666–4675.
4. Kabat, M. M. Tetrahedron Lett. 1993, 34, 8543–8544.
5. Unpublished results.
6. Hashimoto, J.; Tori, M.; Asakawa, Y. Chem. Pharm.
Bull. 1986, 34, 1846.
7. Wada, E.; Kanemasa, S.; Tsuge, O. Bull. Chem. Soc. Jpn.
1989, 62, 860–868.
8. (a) Orrenius, C.; Oehrner, N.; Rottiui, D.; Mattson, A.
Tetrahedron: Asymmetry 1995, 6, 1217–1220; (b) Rotticu,
D.; Halffner, F.; Orrenius, C.; Norin, T.; Hult, K. J. Mol.
Catal. B 1998, 5, 267–272.
+68.9 (c 0.35, CHCl3); H NMR (300 MHz, CDCl3): l
7.24–7.72 (10H, m, ArH
Hz, ArCHꢀCH
3.29 (1H, dd, J=17.1 Hz, CHCH
J=17.4 Hz, CHCH2
6
, ArCH
CO), 5.62 (1H, dd, J=9.6 Hz, ArCH
2CO), 2.90 (1H, dd,
CO); IR (film): 3238, 3059, 2926,
6
ꢀ), 6.75 (1H, d, J=16.5
6
6
),
6
6
1678, 1606, 1351, 1107, 977, 753, 692 cm−1; EIMS
(m/z): 286 (M+) (0.72), 251 (64.56), 233 (24.20), 154
(15.95), 145 (37.40), 139 (45.94), 131 (100.00), 115
(19.21), 103 (72.43), 77 (77.53), 65 (4.71). Anal. calcd
for C17H15ClO2: C, 71.21; H, 5.27. Found: C, 70.83; H,
5.36.
4.6.8.
(5R,1E)-5-Hydroxy-5-(2,4-dichlorophenyl)-1-
phenyl-1-penten-3-one 12h. Colorless solid; mp >210°C
(decomposition); [h]2D7=+92.0 (c 0.95, CHCl3); 1H
NMR (300 MHz, CDCl3): l 7.27–7.66 (9H, m, ArH
ArCHꢀ), 6.74 (1H, d, J=15.9 Hz, ArCHꢀCHCO), 5.55
(1H, dd, J=9.6 Hz, ArCH), 3.25 (1H, dd, J=17.7 Hz,
CHCH2CO), 2.86 (1H, dd, J=18.0 Hz, CHCH2CO);
6 ,
6
6
6
6
6
IR (film): 3274, 3084, 3029, 1677, 1604, 1101, 988, 980,
748, 691 cm−1; EIMS (m/z): 303 (3.78), 267 (12.07), 173
(100.00), 145 (91.13), 131 (85.82), 111 (18.49), 103
(92.33), 85 (5.80), 77 (46.85). Anal. calcd for
C17H14Cl2O2: C, 63.57; H, 4.39. Found: C, 63.19; H,
4.44.
9. Zhang, Y.-H.; Yuan, C.-Y.; Li, Z.-Y. Tetrahedron 2002,
58, 2973–2978.
10. Zhang, Y.-H.; Li, Z.-Y.; Yuan, C.-Y. Tetrahedron Lett.
2002, 43, 3247–3249.
4.6.9. (5R,1E)-5-Hydroxy-5-(2-furyl)-1-phenyl-1-penten-
3-one 12i. Pale yellow oil; [h]2D7=+33.7 (c 0.7, CHCl3);
1H NMR (300 MHz, CDCl3): l 7.55–7.64 (3H, m, ArH
6 ,
ArCH6 ꢀ), 7.40–7.42 (4H, m, ArH6 ), 6.76 (1H, d, J=16.2